Serine protease inhibitors-proline analogs

ABSTRACT

The present invention relates to certain substituted oxadiazole, thiadiazole, and triazole peptoids that are useful as inhibitors of serine proteases, in particular human neutrophil elastase. Serine protease inhibitors of the invention are useful in the treatment of, for example, adult respiratory distress syndrome, septic shock, and myocardial ischemia-reperfusion injury.

This application is a continuation-in-part of U.S. Ser. No. 08/771,317,filed Dec. 6, 1996, now U.S. Pat. No. 5,801,148, which is acontinuation-in-part of U.S. Ser. No. 08/345,820 filed Nov. 21, 1994,now U.S. Pat. No. 5,618,792.

The present invention relates to certain substituted oxadiazole,thiadiazole and triazole peptoids which are useful as inhibitors ofserine proteases.

BACKGROUND PF THE INVENTION

The serine proteases are a class of enzymes which includes elastase,chymotrypsin, cathepsin G, trypsin and thrombin. These proteases have incommon a catalytic triad consisting of Serine-195, Histidine-57 andAspartic acid-102 (chymotrypsin numbering system). Human neutrophilelastase (HNE) is a proteolytic enzyme secreted by polymorphonuclearleukocytes (PMNs) in response to a variety of inflammatory stimuli. Thisrelease of HNE and its extracellular proteolytic activity are highlyregulated and are normal, beneficial functions of PMNs. The degradativecapacity of HNE, under normal circumstances, is modulated by relativelyhigh plasma concentrations of α₁ -proteinase inhibitor (α₁ -PI).However, stimulated PMNs produce a burst of active oxygen metabolites,some of which (hypochlorous acid for example) are capable of oxidizing acritical methionine residue in α₁ -PI. Oxidized α₁ -PI has been shown tohave limited potency as an HNE inhibitor and it has been proposed thatalteration of this protease/antiprotease balance permits HNE to performits degradative functions in localized and controlled environments.

Despite this balance of protease/antiprotease activity, there areseveral human disease states in which a breakdown of this controlmechanism is implicated in the pathogenesis of the condition. Impropermodulation of HNE activity has been suggested as a contributing factorin adult respiratory distress syndrome, septic shock and multiple organfailure. A series of studies also have indicated the involvement of PMNsand neutrophil elastase in myocardial ischemia-reperfusion injury.Humans with below-normal levels of α₁ -PI have an increased probabilityof developing emphysema. HNE-mediated processes are implicated in otherconditions such as arthritis, periodontal disease, glomerulonephritis,dermatitis, psoriasis, cystic fibrosis, chronic bronchitis,atherosclerosis, Alzheimer's disease, organ transplantation, cornealulcers, and invasion behavior of malignant tumors.

There is a need for effective inhibitors of HNE as therapeutic and asprophylactic agents for the treatment and/or prevention ofelastase-mediated problems.

SUMMARY OF THE INVENTION

The present invention provides compounds which are useful as serineprotease inhibitors, including human neutrophil elastase. Thesecompounds are characterized by their relatively low molecular weight,high potency and selectivity with respect to HNE. Additionally, certaincompounds of the invention have demonstrated oral bioavailability asexhibited by their higher blood levels after oral dosing. Oralbioavailability allows oral dosing for use in chronic disease, with theadvantages of self-administration and decreased cost over other means ofadminstration. The compounds described herein can be used effectively toprevent, alleviate or otherwise treat disease states characterized bythe degradation of connective tissue by proteases in humans.

The present invention provides compounds comprising oxadiazole,thiadiazole or triazole ring structures, and can be genericallydescribed by the formula: ##STR1## wherein Z is a serine proteasebinding moiety, preferably an elastase binding moiety, and mostpreferably a human neutrophil elastase binding moiety. Specifically, Zis a carbonyl containing group, preferably an α-amino carbonylcontaining group where the carbonyl carbon is covalently attached to thecarbon of the heterocycle.

R₁ is alkyl, alkenyl or alkynyl optionally substituted with 1 or more,preferably 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino,dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide or --O--(C₅ -C₆)aryl; hydroxyl, amino,alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl,(C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl, (C₅ -C₁₂)arylalkenyl, fused (C₅-C₁₂)aryl-cycloalkyl or alkyl fused (C₅ -C,₁₂)aryl-cycolalkyl optionallycomprising 1-4 heteroatoms selected from N, O and S, and optionallysubstituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio.

X and Y are independently O, S or N, wherein N is optionally substitutedwith alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C₅-C₆)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatomsselected from N, O and S, and optionally substituted with halo, cyano,nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio.Preferably, at least one of X or Y is N. It will be understood thatwhere X or Y is a substituted N, both X and Y are N. Preferably, thecompounds of the present invention comprise 1,2,4-oxadiazole (i.e., X isO; Y is N) or 1,3,4 oxadiazole rings (i.e., X is N; Y is O).

The compounds of the present invention may be conveniently categorizedas Groups I through VI.

In one preferred embodiment, the invention provides compounds of theformula (Group I): ##STR2## wherein X , Y and R₁ are described above; R₂and R₃ are independently or together H; alkyl or alkenyl optionallysubstituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, oramidylguanidine; --RCOR', --RCOOR', --RNR'R"R° or --RC(O)NR'R" where Ris alkyl or alkenyl, and R', R" and R° are independently H, alkyl,alkenyl, cycloalkyl or (C₅ -C₆)aryl; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C₅-C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅ -C₁₂)arylalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S, and optionallysubstituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino,aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl,alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl,arylcarboxamide, alkylthio or haloalkylthio;

A is a direct bond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --NH--S(O)₂ --,--OC(O)--, --C-- or an amino acid selected from, but not limited to,proline, isoleucine, cyclohexylalanine, cysteine optionally substitutedat the sulfur with alkyl, alkenyl or phenyl optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, tyrosine, serine or threonine optionallysubstituted with alkyl or aryl; histidine, methionine, valine,norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine,glutamine, ornithine and lysine optionally substituted at the side chainnitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkylor aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkylor alkyl fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S; and

R₄ is H, alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C₅-C₁₂)aryl, (C₅ -C₁₂)arylalkyl, fused (C₅ -C₁₂)aryl-cycloalkyl or fusedalkyl (C₅ -C₁₂)aryl-cycloalkyl optionally comprising one or moreheteroatoms selected from N, O and S, and optionally substituted withalkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl,alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy,carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido,alkylthio or haloalkylthio or is absent.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. Preferably, R₄ --A is anarylalkyloxycarbonyl such as benzyloxycarbonyl; alkoxycarbonyl,arylsulfonyl, alkylsulfonyl or alkyl.

Preferably, R₂ and R₃ are alkyl such as methyl or isopropyl, or H. Inone preferred embodiment, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as an α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁ -C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

The present invention further provides compounds of the formula (GroupII): ##STR3## wherein X, Y, R₁, R₂ and R₃ are as described above;

B is --S(O)₂ --, --C(O)--, --OC(O)-- or --CH₂ C(O)--;

R₆ is ##STR4## wherein R'₂ and R'₃ are independently or together H;alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio,alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl,dialkylguanidinyl, guanidinyl, or amidylguanidine; --RCOR', --RCOOR',--RNR'R"R° or --RC(O)NR'R" where R is alkyl or alkenyl, and R', R" andR° are independently H, alkyl, alkenyl, cycloalkyl or (C₅ -C₆)aryl; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl,alkyl-thioaryl, alkyl-aminoaryl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S, and optionally substituted with halo, cyano, keto, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,amidine,alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio;

R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S,and optionally substituted with halo or alkyl;

R₁₄ is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl, alkylfused aryl-cycloalkyl or aryloxycarboxamide optionally comprising 1 ormore heteroatoms selected from N, O and S, and optionally substitutedwith alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl,alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio orhaloalkylthio;

R₁₅ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S;and

W is O or S; or C or N optionally substituted with H, alkyl or aryl.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. According to several preferredembodiments, R₁₃ is an optionally substituted phenyl or benzyl; pyridyl,piperidinyl, alkyl or H or a fused ring system such as3,4-methylenedioxybenzyl; R₁₄ is optionally substituted amino or anarylalkyloxycarboxamide such as benzyloxycarboxamide; and R₁₅ is H orhalo.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁ -C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

The present invention also provides compounds of the formula (GroupIII): ##STR5## wherein X, Y, R₁, R₂, R₃ and B are as described above;and R₆ is of formula (I): ##STR6## where m is O or 1; n is 0 or 1; D isa direct bond or an amino acid selected from, but not limited to,proline, isoleucine, cyclohexylalanine, cysteine optionally substitutedat the sulfur with alkyl, alkenyl or phenyl optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,homophenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, tyrosine, serine or threonine optionallysubstituted with alkyl or aryl; histidine methionine, valine, norvaline,norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,ornithine and lysine optionally substituted at the side chain nitrogenwith alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkylor aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkylor alkyl fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S;

A is a direct bond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --OC(O)-- or--C--; and

R₁₄ is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteratomsselected from N, O and S, and optionally substituted with alkyl, halo,alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,arylcarboxamide, alkylthio or haloalkylthio.

Alternatively, R₆ is of formula (II): ##STR7## where W is S or O;

R₈ is alkylamino, dialkylamino or amino;

R₉ is H, alkyl or halo.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. According to one embodiment, where R₆ isof formula (I), m is 1, n is 0. In another embodiment, m and n are 1.Preferably, R₁₄ is benzyl, A is --OC(O)-- and D is Val.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁ -C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

According to one embodiment, W is S; R₈ is amino and R₉ is H.

In yet a further embodiment of the invention of Group (III) compounds,R₆ is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl. According to oneembodiment, R₆ -B is Cbz.

The present invention further provides compounds of the formula (GroupIV): ##STR8## wherein X, Y, R₁, R₂ and R₃ are as described above;

R₁₀ is (C₅ -C₆)aryl, (C₅ -C₆)arylalkyl, (C₅ -C₆)arylalkenyl, cycloalkyl,fused aryl-cycloalkyl optionally comprising one or more heteroatomsselected from N, S and non-peroxide O, and optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, alkylthio or haloalkylthio;

D is a direct bond, --C(O)--, or an amino acid selected from, but notlimited to, proline, isoleucine, cyclohexylalanine, cysteine optionallysubstituted at the sulfur with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;phenylalanine, homophenylalanine, dehydrophenylalanine,indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acidoptionally substituted with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;tryptophan, tyrosine, serine or threonine optionally substituted withalkyl or aryl; histidine methionine, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine andlysine optionally substituted at the side chain nitrogen with alkyl,alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteratomsselected from N, O and S;

A is a direct bond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --NH--S(O)₂ --,--S(O)₂ --NH--, --OC(O)NH--, --OC(O)-- or --C--; and R₁₄ is as describedabove.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N. Preferably, D is Val, A is --OC(O)-- andR₁₄ is aryl or arylalkyl such as benzyl. In a preferred embodiment, R₁₀is (C₅ -C₆)aryl or (C₅ -C₆)arylalkyl, preferably benzyl, or a fusedaryl-cycloalkyl such as an indanyl group. According to another preferredembodiment, D is --C(O)--, and R₁₄ -A is pyrrole.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁ -C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

The present invention additionally provides compounds of the formula(Group V): ##STR9## wherein X, Y, R₁, R₂, R₃, R'₂ and R'₃ are asdescribed above; and

R₁₁, R₁₂ and E together form a monocyclic or bicyclic ring comprising5-10 atoms selected from C, N, S and O; said ring containing 1 or moreketo groups; and optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, alkylthio,haloalkylthio; cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅-C₁₂)aryl, (C₅ -C₁₂)arylalkyl, ((C₅ -C₁₂)arylalkyl)OC(O)NH-- or (C₅-C₁₂)arylalkenyl optionally comprising one or more heteroatoms selectedfrom N, S and non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,--C(O)O(alkyl), --C(O)(alkyl), alkylcarboxamido, alkylthio orhaloalkylthio.

In a preferred embodiment, X is N and Y is O. In another preferredembodiment, X is O and Y is N.

Preferably, R₂ is isopropyl and R₃ is H.

In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁ -C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

According to one embodiment of the invention, R₁₁, R₁₂, and E togetherform a ring structure of formulas (I) or (Ia): ##STR10## wherein A is asdescribed above for Group (IV); V₁, V₂, V₃ and V₄ are independently ortogether C or N;

where V₃ is C; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl,alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl,cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl optionally comprising 1 or more heteroatoms selectedfrom O, N and S, and optionally substituted with halo or alkyl;

R₁₄ is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl, arylalkylxoxycarbonyl or arylalkylcarboxamideoptionally comprising 1 or more heteratoms selected from N, O and S, andoptionally substituted with alkyl, halo, alkoxy, amino, alkylamino,dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy,alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio orhaloalkylthio; and

W₁, W₂ and W₃ are independently selected from N optionally substitutedwith alkyl; C, S and O.

According to one preferred embodiment, V₄ is N; and V₁, V₂ and V₃ are C.Preferably, R₁₃ is H or halo; R₁₄ -A is CbzNH, amino or H; and R'₂ andR'₃ are H. Preferably, R₁₁, R₁₂ and E together form a ring of formula(I). In a particular embodiment, R₁₃ is H or F; and R₁₄ -A-- is H or H₂N--. Where R₁₁, R₁₂ and E together form a ring of formula (Ia), W₁ ispreferably S, and W₂ and W₃ are C.

In another embodiment, R₁₁, R₁₂ and E together form a ring of formula(II) ##STR11## wherein A, R₁₃ and R₁₄ are as described above;

Preferably, R'₂ and R'₃ are H. According to one embodiment, R₁₃ is1-piperidinyl; and R₁₄ -A is CbzNH. Alternatively, R₁₃ is H; and R₁₄ -Ais amino, alkylamino or dialkylamino. In another preferred embodiment,R₁₃ is halo; and R₁₄ -A is CH₃ --O--C(O)--. In yet another embodiment,R₁₃ is H; and R₁₄ -A is CbzNH.

According to another embodiment of the invention, R₁₁, R₁₂ and E form aring of formula (III) or (IV): ##STR12## wherein A is a direct bond,--C-- or --C(O)--;

R₁₃, R₁₄ and R₁₅ are as defined above.

According to a particular embodiment, R₁₁, R₁₂ and E form a ring offormula (III); and --A--R₁₃ is --C(O)phenyl; R₁₄ is H; and R'₂ and R'₃are H.

In another embodiment, R₁₁, R₁₂ and E form a ring of formula (IV); and--A--R₁₃ is --C(O)phenyl; R₁₅ is H; and R'₂ and R'₃ and H.

In another embodiment of the invention, R₁₁, R₁₂ and E form a ring offormula (V): ##STR13## wherein W is S, SO, SO₂ or C;

n is 0, 1 or 2;

R₁₃ and R₁₄ are defined above; and

G is --NHC(O)--, --OC(O)NH--, --C(O)--, --NHS(O)₂ -- or a direct bond.

According to one embodiment, n is 0 and W is S, where preferably R₁₄ --Gis H. Preferably, R₁₃ is optionally substituted benzyl or phenyl.

In another embodiment, n is 1 and W is C. Preferably, R₁₄ -G is anarylalkyloxycarboxamide, for example, CbzNH--. In a preferredembodiment, R₁₃ is H or phenyl substituted with halo. Preferably, R'₂and R'₃ are H.

The invention further provides compounds wherein R₁₁, R₁₂ and E form aring of formulas (VI), (VIa), (VII) or (VIII): ##STR14## wherein R₁₃ isas defined above, or is ═CHR₁₅ or R₁₅ where R₁₅ is pyridinyl, phenyl orbenzyl optionally substituted with halo, dialkylamino or --C(O)OCH₃ ;

R₁₄ and R'₁₄ are independently or together H, alkyl, alkenyl, CH₃C(O)--; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fusedaryl-cycloalkyl or alkyl fused aryl-cycloalkyl, aryloxycarbonyl orarylalkyloxycarbonyl optionally comprising 1 or more heteratoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide,alkylthio or haloalkylthio; and

R₁₆, R₁₇, R'₁₆ and R'₁₇ are independently or together H, alkyl, alkenyl,alkylthio, alkylthioalkyl; or cycloalkyl, cycloalkenyl, alkylcycloalkyl,aryl, arylalkyl or arylalkenyl optionally substituted with guanidine,carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine,dialkylguanidine or amidine.

Preferred compounds are of formula (VI) or (VIa) where R₁₃ is ═CHR₁₅ orR₁₅ ; and R₁₄ is H, alkyl, CH₃ C(O)--, Cbz or benzyl optionallysubstituted with alkyl, halo or alkylamino; or 3,4-methylenedioxybenzylor 3,4-ethylenedioxybenzyl; and R'₂ and R'₃ are H. Preferably, R₁₃ is═CHR₁₅ where R₁₅ is phenyl or benzyl optionally substituted with halo or--C(O)CH₃.

In a further embodiment, R₁₁, R₁₂ and E form a ring of formula (IX) or(IXa): ##STR15## wherein U, V, W and Y are independently or together N,C, C(O), N(R₁₃) where R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteroatomsselected from O, N and S, and optionally substituted with halo or alkyl;N(R₁₄) where R₁₄ is H, alkyl, alkenyl, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteratoms selected from N, O and S, andoptionally substituted with alkyl, halo, alkoxy, amino, alkylamino,dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy,alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio orhaloalkylthio; or C(R₁₆)(R₁₇) where R₁₆ and R₁₇ are independently ortogether H, alkyl, alkylthio, alkylthioalkyl; a carboxylic acid ester ofthe formula --(CH₂)_(m) C(O)OR or an N-substituted alkylamide of theformula --(CH₂)_(m) C(O)NRR' where m is 1 to 6 and R and R' areindependently or together H or alkyl; or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising one or more heteroatoms selected from N, S andnon-peroxide O and optionally substituted with amino, alkylamino,dialkylamino, guanidine, carboalkoxy, keto, hydroxyl, alkyl, haloalkyl,alkylthio, alkylguanidine, dialkylguanidine or amidine; or together forma cyclic ring structure comprising 4-8 atoms selected from C, N, O andS.

In one preferred embodiment, U is C(R₁₆)(R₁₇), V is N, W is N(R₁₄) and Yis C(O), where preferably R'₂ and R'₃ are H; R₁₆ is phenyl or benzyl;R₁₇ is H; and R₁₄ is H or benzyl optionally substituted with alkyl,halo, or alkylamine.

In another preferred embodiment, U is C(O); V is N, W is N, N(R₁₃) orN(R₁₄); and Y is C(R₁₆)(R₁₇), where preferably R'₂ and R'₃ are H; R₁₄ isH; R₁₆ is H, alkyl, optionally substituted aryl or arylalkyl, preferablybenzyl or phenyl optionally substituted with dialkylamino or hydroxyl;pyridinyl, methylene pyridinyl; fused aryl such as an indolyl; or acarboxylic acid ester or N-substituted alkyl amide, as defined above;and R₁₇ is H, alkyl, succinimidyl, aryl or arylalkyl.

In yet another preferred embodiment, U is C(O), V is N, W is N, N(R₁₃)or N(R₁₄); and Y is N(R₁₃), where preferably R'₂ and R'₃ are H; W is NH;R₁₃ is arylalkyl; and R₁₄ is H.

In a further embodiment, U is C(R₁₆)(R₁₇); V is N; W is N or N(R₁₃); andY is C(O). Preferably, R₁₃ and R₁₆ are aryl; and R₁₇ is H.

Where R₁₁, R₁₂ and E form a ring of formula (IXa); W is typically N(R₁₃)where R₁₃ is aryl or cycloalkyl such as piperidinyl.

In another embodiment, R₁₆ and R₁₇ form a cyclic ring structure, such asa cyclopentyl or cyclohexyl group.

The invention further provides compounds of the formula (Group VI):##STR16## wherein X, Y, R₁, R₂ and R₃ are as described above, and R₁₁,R₁₂ and E together form a ring of formula (X): ##STR17## where U and Vare independently or together N, C, N(R₁₃) where R₁₃ is H, alkyl,alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino,dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fusedaryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1or more heteroatoms selected from O, N and S; or C(R₁₆)(R₁₇) where R₁₆and R₁₇ are as defined above; and and n is 1 or 2.

The present invention further provides methods of synthesizing compoundsof formula (A): ##STR18## wherein Z' is defined below;

R₁ is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl;-alkyl--C(O)OCH₃ ; alkylamino, dialkylamino, alkyldialkylamino; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅-C₁₂)arylalkyl, (C₅ -C₁₂)arylalkenyl, fused (C₅ -C₁₂)aryl-cycloalkyl orfused (C₅ -C₁₂)aryl-cyclalkylalkyl optionally comprising 1-4 heteroatomsselected from N, O and S, and optionally substituted with halo, cyano,nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl,arylcarboxamide, alkylthio or haloalkylthio;

X and Y are independently O, S or N, wherein N is optionally substitutedwith alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C₅-C₆)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatomsselected from N, O and S, and optionally substituted with halo, cyano,nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; and

R₂ and R₃ are independently or together H; alkyl or alkenyl optionallysubstituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, oramidylguanidine; --RCOR', --RCOOR', --RNR'R"R° or --RC(O)NR'R" where Ris alkyl or alkenyl, and R', R" and R° are independently H, alkyl,alkenyl, cycloalkyl or (C₅ -C₆)aryl; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C₅-C₁₂)aryl, (C₅ -C₁₂)arylalkyl or (C₅ -C₁₂)arylalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S, and optionallysubstituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino,aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl,alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl,arylcarboxamide, alkylthio or haloalkylthio;

comprising the steps of:

(a) reacting a compound of formula (B): ##STR19## wherein M is Li orMgBr, with an aldehyde of formula (C): ##STR20## where [PrG₁ ] is aprotecting group; (b) removing the protecting group from the resultingalcohol (D)

(c) coupling the alcohol obtained from step (b) with an acid of formula(E):

    Z'--COOH                                                   (E)

and

(d) oxidizing the resulting product and further, if desired, removingthe protecting group to yield the final compound.

According to one embodiment, the protecting group [PGR₁ ] is removedfrom alcohol (D) by reacting the aldehyde of formula (C) withhydrochloric acid in dioxane. The protecting group [PGr₁ ] may be anysuitable group, preferably Boc.

According to another embodiment, the oxidation step of (d) is performedusing Dess Martin reagent.

In a further embodiment, the compound of formula (B) is synthesized by:

(e) treating an acid of the formula (R₁)COOH with thionyl chloride oroxalyl chloride;

(f) treating the resulting acid chloride with hydrazine to yield ahydrazide of the formula (R₁)CONHNH₂ ;

(g) reacting the hydrazide with triethyl orthoformate or trimethylorthoformate and TsOH to yield a oxadiazole of the formula (F):##STR21## and (h) treating the oxadiazole with butyllithium and further,is desired, reacting with MgBr.OEt₂ to yield the compound B.

In one embodiment, Z' is ##STR22## wherein A is a direct bond, --C(O)--,--NH--C(O)--, --S(O)₂ --, --NH--S(O)₂ --, --OC(O)--, --C-- or an aminoacid selected from proline, isoleucine, cyclohexylalanine, cysteineoptionally substituted at the sulfur with alkyl, alkenyl or phenyloptionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine,indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acidoptionally substituted with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;tryptophan, tyrosine, serine or threonine optionally substituted withalkyl or aryl; histidine, methionine, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine andlysine optionally substituted at the side chain nitrogen with alkyl,alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteroatomsselected from N, O and S; and

R₄ is H, alkyl, alkenyl, or alkynyl; or cycloalkyl, alkylcycloalkyl, (C₅-C₁₂)aryl, (C₅ -C₁₂)arylalkyl, fused (C₅ -C₁₂)aryl-cycloalkyl or fused(C₅ -C₁₂)aryl-cycloalkylalkyl optionally comprising one or moreheteroatoms selected from N, O and S, and optionally substituted withalkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl,alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy,carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido,alkylthio or haloalkylthio or is absent; or

Z' may be ##STR23## wherein R'₂ and R'₃ are independently or together H;alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio,alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl,dialkylguanidinyl, guanidinyl or amidylguanidine; --RCOR', --RCOOR',--RNR'R"R° or --RC(O)NR'R" where R is alkyl or alkenyl, and R', R" andR° are independently H, alkyl, alkenyl, cycloalkyl or (C₅ -C₆)aryl; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl,alkyl-thioaryl, alkyl-aminoaryl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S, and optionally substituted with halo, cyano, keto, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio;

R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S,and optionally substituted with halo or alkyl;

R₁₄ is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl, alkylfused aryl-cycloalkyl or aryloxycarboxamide optionally comprising 1 ormore heteroatoms selected from N, O and S, and optionally substitutedwith alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl,alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio orhaloalkylthio; and

R₁₅ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S.

In yet a further embodiment, Z' is: ##STR24## where m is 0 or 1; n is 0or 1; D is a direct bond or an amino acid selected from proline,isoleucine, cyclohexylalanine, cysteine optionally substituted at thesulfur with alkyl, alkenyl or phenyl optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy,haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine,dehydrophenylalanine, indoline-2-carboxylic acid;tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, tyrosine, serine or threonine optionallysubstituted with alkyl or aryl; histidine methionine, valine, norvaline,norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,ornithine and lysine optionally substituted at the side chain nitrogenwith alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkylor aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkylor alkyl fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S; and

A' is a direct bond, --C(O)--, --NH--C(O)--, --S(O)₂ --, --NH--S(O)₂ --,--OC(O)--or --C--.

In yet another embodiment, Z' is: ##STR25## where W is S or O;

R₈ is alkylamino, dialkylamino or amino; and

R₉ is H, alkyl or halo; or

Z' is: ##STR26## wherein R₁₀ is (C₅ -C₆)aryl, (C₅ -C₆)arylalkyl, (C₅-C₆)arylalkenyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl oralkyl fused aryl-cycloalkyl optionally comprising one or moreheteroatoms selected from N, S and non-peroxide O, and optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio.

In a preferred embodiment, Z' is: ##STR27## wherein R₁₁, R₁₂ and Etogether form a monocyclic or bicyclic ring comprising 5-10 atomsselected from C, N, S and O; said ring containing 1 or more keto groups;and optionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅-C₁₂)arylalkyl, ((C₅ -C₁₂)arylalkyl)OC(O)NH-- or (C₅ -C₁₂)arylalkenyloptionally comprising one or more heteroatoms selected from N, S andnon-peroxide O, and optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, --C(O)O(alkyl),--C(O)(alkyl), alkylcarboxamide, alkylthio or haloalkylthio.

In a preferred embodiment, the invention provides a method ofsynthesizing a compound of formula (G): ##STR28## wherein T is H or NH₂;

R₁ is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl;a carboxylic acid ester such as -alkyl--C(O)OCH₃ ; alkylamino,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl, (C₅-C₁₂)arylalkenyl, fused (C₅ -C₁₂)aryl-cycloalkyl or fused (C₅-C₁₂)aryl-cyclalkylalkyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S, and optionally substituted with halo, cyano, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl,alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, (C₅ -C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide,alkylthio or haloalkylthio; and

Ar is an aryl or arylalkyl optionally substituted with H, alkyl, amino,alkylamino, dialkylamino, halo or hydroxyl;

comprising the steps of:

(a) reacting a compound of formula (B): ##STR29## wherein M is Li orMgBr; with an aldehyde of formula (C): ##STR30## where [PrG₁ ] is aprotecting group; (b) removing the protecting group from the resultingalcohol (D)

(c) coupling the alcohol obtained from step (b) with an acid of formula(H): ##STR31## wherein T' is H or [PGr₂ ]NH, where [PGr₂ ] is aprotecting group;

(d) oxidizing the resulting product to yield a ketone of formula (J):##STR32## and further, when T' is [PGr₂ ]NH, (e) removing the protectinggroup [PGr₂ ] to yield the compound of formula (G). Preferably, [PGr₂ ]is Cbz.

As used herein, the term "optionally substituted" means, whensubstituted, mono to fully substituted.

As used herein, the term "independently" means that the substituents maybe the same or different.

As used herein, the term "alkyl" means C₁ -C₁₅, however, preferably C₁-C₈.

As used herein, the term "alkenyl" means C₁ -C₁₅, however, preferably C₁-C₈.

As used herein, the term "alkynyl" means C₁ -C₁₅, however, preferably C₁-C₈.

It will be understood that alkyl, alkenyl and alkynyl groups, whethersubstituted or unsubstituted, may be linear or branched.

As used herein, the term "aryl," unless otherwise stated, means arylgroups preferably comprising 5 to 12 carbons, and more preferably 5 to 6carbons. Unless otherwise indicated, the term includes both mono- andbi-cyclic fused ring systems. As used herein, where the term "arylalkyl"is defined by the general formula (C_(x) --C_(y))arylalkyl, x and yrefer to the number of carbons making up the aryl group. The alkyl groupis as defined above. The term include mono-substituted alkyl groups(e.g., benzyl), as well as di-substituted alkyl groups such as-alkyl(aryl)₂ (e.g., --CH(phenyl)₂). The terms arylalkyl and alkyl fusedarylcycloalkyl include (α,α)-disubstituted groups such as, for example,(α,α)-disubstituted benzyl and (α,α)-disubstituted3,4-methylenedioxybenzyl groups, wherein the a substituents arepreferably alkyl groups such as methyl, ethyl or propyl. Specificexamples include (α,α)-dimethylbenzyl and(α,α)-dimethyl-3,4-methylenedioxybenzyl.

As used herein, the term "arylalkenyl" includes aryl groups where thealkenyl group comprises 1-3 or more double bonds. Exemplary arylalkenylgroups include ═CH--CH₂ -aryl and --CH═CH-aryl, where aryl is preferablyphenyl.

As used herein, the term "cycloalkyl," unless otherwise stated, meanscycloalkyl groups preferably comprising 3 to 12 carbons, and morepreferably 3 to 6 carbons. Unless otherwise indicated, the term includesboth mono-, bi- and tri-cyclic fused ring systems.

As used herein, the term "Cbz" means benzyloxycarbonyl.

As used herein, the term "carboxamide" is synonymous with amide; i.e., agroup of the formula --NHC(O)--.

As used herein, the term "oxycarboxamide" means a group of the formula--O--C(O)NH--.

As used herein, the term "oxycarbonyl" means a group of the formula--OC(O)--.

Pharmaceutically acceptable salts of the compounds described above arewithin the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 2 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 3 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 4 is a schematic representation of the synthesis of compounds ofGroup I.

FIG. 5 is a schematic representation of the synthesis of compounds ofGroup II.

FIG. 6 is a schematic representation of the synthesis of compounds ofGroup II.

FIG. 7 is a schematic representation of the synthesis of compounds ofGroup II.

FIG. 8 is a schematic representation of the synthesis of compounds ofGroup III.

FIG. 9 is a schematic representation of the synthesis of compounds ofGroup III.

FIG. 10 is a schematic representation of the synthesis of compounds ofGroup IV.

FIG. 11 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 12 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 13 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 14 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 15 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 16 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 17 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 18 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 19 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 20 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 21 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 22 is a schematic representation of the synthesis of compounds ofGroup V.

FIG. 23 shows the activity of certain compounds of Group I.

FIG. 24 shows the activity of certain compounds of Group I.

FIG. 25 shows the activity of certain compounds of Group I.

FIG. 26 shows the activity of certain compounds of Group I.

FIG. 27 shows the activity of certain compounds of Group I.

FIG. 28 shows the activity of certain compounds of Group II and III.

FIG. 29 shows the activity of certain compounds of Groups II, III andIV.

FIG. 30 shows the activity of certain compounds of Group V.

FIG. 31 shows the activity of certain compounds of Group V.

FIG. 32 shows the activity of certain compounds of Group V.

FIG. 33 shows the activity of certain compounds of Group V.

FIG. 34 shows the activity of certain compounds of Group V.

FIG. 35 shows the activity of certain compounds of Group V.

FIG. 36 shows the activity of certain compounds of Group V.

FIG. 37 shows the activity of certain compounds of Group V.

FIG. 38 shows the activity of certain compounds of Group V.

FIG. 39 is a schematic representation of the synthesis of certaincompounds of the invention.

DETAILED DESCRIPTION

The compounds of the present invention have been found to be potentinhibitors of the serine protease human neutrophil elastase (HNE). Theyare reversible inhibitors that presumably form a transition stateintermediate with the active site serine residue. The compounds arecharacterized by their low molecular weights, high selectivity withrespect to HNE and stability regarding physiological conditions.Therefore, the compounds can be implemented to prevent, alleviate and/orotherwise treat diseases which are mediated by the degradative effectsassociated with the presence of HNE. Their usage is of particularimportance as they relate to various human treatment in vivo but mayalso be used as a diagnostic tool in vitro.

The present invention provides, but is not limited to, specificembodiments set forth in the Examples as well as those set forth below.##STR33##

The nomenclature for the above embodiments is as follows (although themajority of the embodiments disclosed indicate the stereochemistry ofthe 2-methylpropyl group having the (S)-configuration, it will beunderstood that both the (R)-configuration and the racemic (R,S) arewithin the scope of the invention):

CE-21572-Oxo-5-(phenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2158 3-(S)-[(Benzyloxycarbonyl)amino-(5,6phenyl-ε-lactam]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2159 2-(R,S)-[(Methylene-4-pyridyl)piperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21603-(R,S)-[(Benzyloxycarbonyl)amino-δ-lactam]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2161(Pyridyl-3-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-2162 4-[1-(2-N-Morpholino)ethyl-3-(R)-benzylpiperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2163Methylsulfonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-2164(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

CE-2165N-Acetyl-2-(L)-(2,3-dihydro-1H-indole)-N[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

CE-21661-Phenyl-1,2,4-triazolidine-3,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2168Phenylsulfonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-21701-[2-(5-[3-Methylbenzyl]-1,3,4-oxadiazolyl]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-one

CE-2171(3-Pyridylcarbonyl)-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-2172Methylsulfonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-21731-(3-Morpholinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-21744-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21761-Benzyl-1,2,4-triazolidine-3,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2177(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-2178(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-21795-(R,S)-Phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21801-(N-Morpholinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-21811-(N-Morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2182 5-(R,S)-Phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2183Benzyloxycarbonyl-L-(1,2,3,4-tetrahydroisoquinoline)-3-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]amide

CE-21841-(N-Morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-21854-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-21864-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-21874-[1-(3,4-Ethylenedioxybenzyl)-3-(S)-benzyl-piperazine-2,5-dione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21881-Benzyl-4-(S)-benzyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21891-Benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2190[1-Benzyloxycarbonyl-5-(R)-benzylpiperazin-3-one]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21911-Benzyl-4-(S)-benzyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-21921-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-21931-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2194[4-(R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2195(Pyrrole-2-carbonyl)-N-(1-(R,S)-indanyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

CE-2196(6-(R)-Benzylpiperazin-2-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-21974-[1-(3,4-Methylenedioxybenzyl)-3-(R)-benzylpiperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-21984-(R,S)-Phenyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2200[4-(R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2202Isopropyloxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-2203[4-(R)-(3-pyridylmethylene)]-2,5-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22041-Benzyloxycarbonyl-(2-(R)-phenylpiperazin-5-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2205[4-(R)-(3-pyridylmethyl)]-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2206[4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl]-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2207Isopropyloxycarbonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-2208(2-(R)-Phenylpiperazin-5-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2209[4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl]-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2210(N-Benzylcarbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

CE-2211(R,S)-3-Amino-2-oxo-5-phenyl-1,4-(6-2'-chlorobenzodiazepine)-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-propyl]acetamide

CE-22123-[1-(4-Piperidine)]-benzimidazolidin-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2213Methyloxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]L-prolinamide

CE-2214 Methyloxycarbonyl-L-valyl-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

CE-22151,4-Quinazolin-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2216[4-(R,S)-(2-Pyridyl)-4-(R,S)-methyl]-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22172-Oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2218(R,S)-3-Amino-2-oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3methylpropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-22191,4-Quinazolin-2-one-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2220(2S,5S)-5-Amino-1,2,4,5,6,7-hexahydroazepino-[3.2.1]-indole-4-one-carbonyl-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]amide

CE-2221(R,S)-3-Amino-2-oxo-5-phenyl-1,4-benzodiazepine-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2223(R,S)-3-Amino-2-oxo-5-phenyl-1,4-(2'-chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2224(R,S)-3-Amino-2-oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2225 (R,S)-3-Amino-2-oxo-5-methyl-1,4-(2',3'-methylenedioxy)benzodiazepine)-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2226(R,S)-3-Amino-2-oxo-5-methyl-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-22274-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22283-(R,S)-Amino-quinolin-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2229(R,S)-3-Amino-2-oxo-5-(2-chlorophenyl)-1,4-(2'-chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2230(R,S)-3-Benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-1,4-(2'-chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-22314-Spirocyclopentane-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2232Benzyloxycarbonyl-L-valyl-N-(phenyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

CE-22332-Oxo-5-(4-piperidinyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22342-(2-Pyridyl)-benzimidazole-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2235(R,S)-3-Amino-2-oxo-5-methyl-1,4-(2',3'-dimethoxybenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

CE-2236(R,S)-3-Amino-2-oxo-5-methyl-1,4-(1-thiophenodiazepine)-N-[1-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-2237 2-Oxo-5-(4-trifluoromethylphenyl)-1,4benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22382,5-Imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22394,4-Dimethyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22404-(S)-(2-Isopropyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22414-Spirocyclohexane-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22422-Oxo-5-phenyl-1,4-(4'-methylbenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22434-(R)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22442-Oxo-5-methyl-1,4-(1-thiophenodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22452-Oxo-5-methyl-1,4-(2-phenyl-1-thiophenodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22464-(R)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22474-(R)-(2-N,N-Dimethylcarboxamido)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22482-Oxo-5-(3,4-methylendioxyphenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22494-(R)-(3-Carbomethoxy)propyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22502-Oxo-5-(2-methoxyphenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22512-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22524,4-Diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22534-Spiro-(2-indanyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22542-[(4-Fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22554-(R)-(4-Hydroxybenzyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22564-(R)-(4-Hydroxybenzyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22574-(R)-(2-Imidazolyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetarnide

CE-22582-Oxo-5-phenyl-1,4-(2'-dimethylaminobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22594,4-Diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22602-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22612-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22622-[5-Arnino-6-oxo-2-thiophenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

CE-22632-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6902-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6912-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6922-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6932-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

ONO-PO-6942-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6952-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6962-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6972-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6982-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-6992-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7002-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-701 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-dihydroxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7022-[5-(Methylsulfonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-2-methylpropyl]acetamide

ONO-PO-7032-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7042-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7052-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7062-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7072-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7084-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7094-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-710Methylsulfonyl-L-valyl-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

ONO-PO-7112-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,.alpha.-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7122-[5-Arnino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetarnide

ONO-PO-713Methylsulfonyl-L-valyl-N-[1-(2-[5-(iert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

ONO-PO-7142-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7152-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(.alpha.,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7162-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7172-Oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7182-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

ONO-PO-7194-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7204-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7212-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetarnide

ONO-PO-7222-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7234-(R)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7244-(R)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7252-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7262-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7272-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

ONO-PO-7282-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7292-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

ONO-PO-7302-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7312-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-α,α-dimethylbenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7322-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

ONO-PO-7332-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

ONO-PO-7342-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7352-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

ONO-PO-7362-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

ONO-PO-7372-[6-Oxo-2-phenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

The compounds of the present invention are not limited to use forinhibition of human elastase. Elastase is a member of the class ofenzymes known as serine proteases. This class also includes, forexample, the enzymes chymotrypsin, cathepsin G, trypsin and thrombin.These proteases have in common a catalytic triad consisting ofSerine-195, Histidine-57 and Aspartic acid-102 (chymotrypsin numberingsystem). The precise hydrogen bond network that exists between theseamino acid residues allows the Serine-195 hydroxyl to form a tetrahedralintermediate with the carbonyl of an amide substrate. The decompositionof this intermediate results in the release of a free amine and theacylated enzyme. In a subsequent step, this newly formed ester ishydrolyzed to give the native enzyme and the carboxylic acid. It is thiscarboxyl component that helps characterize the specificity for theenzyme. In the example in which the carboxyl component is a peptide, thealpha-substituent of the amino acid is predominately responsible for thespecificity toward the enzyme. Utilizing the well accepted subsetnomenclature by Schechter and Berger (Biochem. Biophy. Res. Commun.,27:157 (1967) and Biochem. Biophys. Res. Commun., 32:898 (1968)), theamino acid residues in the substrate that undergo the cleavage aredefined as P_(l) . . . P_(n) toward the N-terminus and P_(l) ' . . .P_(n) ' toward the C-terminus. Therefore, the scissile bond is betweenthe P_(l) and the P_(l) ' residue of the peptide subunits. A similarnomenclature is utilized for the amino acid residues of the enzyme thatmake up the binding pockets accommodating the subunits of the substrate.The difference is that the binding pocket for the enzyme is designatedby S_(l) . . . S_(n) instead of P_(l) . . . P_(n) as for the substrate.

The characteristics for the P_(l) residue defining serine proteinasespecificity is well established. The proteinases may be segregated intothree subclasses: elastases, chymases and tryptases based on thesedifferences in the P_(l) residues. The elastases prefer small aliphaticmoieties such as valine whereas the chymases and tryptases prefer largearomatic hydrophobic and positively charged residues respectively.

One additional proteinase that does not fall into one of thesecategories is propyl endopeptidase. The P_(l) residue defining thespecificity is a proline. This enzyme has been implicated in theprogression of memory loss in Alzheimer's patients. Inhibitorsconsisting of α-keto heterocycles have recently been shown to inhibitpropyl endopeptidase; Tsutsumi et al., J. Med. Chem., 37: 3492-3502(1994). By way of extension, α-keto heterocycles as defined herein allowfor an increased binding in P' region of the enzyme.

                  TABLE 1                                                         ______________________________________                                        P.sub.1  Characteristics for Proteinase Specificity                             Proteinase Class                                                                          Representative Enzyme                                                                          P.sub.1  Characteristic                        ______________________________________                                        Elastases Human Neutrophil Elastase                                                                      small aliphatic                                        residues                                                                    Chymases alpha-Chymotrypsin, aromatic or large                                 Cathepsin G hydrophobic residues                                             Tryptases Thrombin, Trypsin, positively charged                                Urokinase, Plasma Kallikrein, residues                                        Plasminogen Activator,                                                        Plasmin                                                                      Other Prolyl Endopeptidase proline                                          ______________________________________                                    

Since the P_(l) residue predominately defines the specificity of thesubstrate, the present invention relates to P_(l) -P_(n) 'modifications, specifically, certain alpha-substituted keto-heterocyclescomposed of 1,3,4 oxadiazoles, 1,2,4-oxadiazoles, 1,3,4-thiadiazoles,1,2,4-thiadiazoles, 1-substituted, and 4-substituted 1,2,4-triazoles. Byaltering the alpha-substituent and the substituent on the heterocycle,the specificity of these compounds can be directed toward the desiredproteinase (e.g., small aliphatic groups for elastase).

The efficacy of the compounds for the treatment of various diseases canbe determined by scientific methods which are known in the art. Thefollowing are noted as examples for HNE mediated conditions:

for acute respiratory distress syndrome, the method according to humanneutrophil elastase (HNE) model (AARD, 141:227-677 (1990)); theendotoxin induced acute lung injury model in minipigs (AARD, 142:782-788(1990)); or the method according to human polymorphonuclearelastase-induced lung hemorrage model in hamsters (European PatentPublication No. 0769498) may be used;

in ischemia/reperfusion, the method according to the canine model ofreperfusion injury (J. Clin. Invest., 81: 624-629 (1988)) may be used.

The compounds of the present invention, salts thereof, and theirintermediates can be prepared or manufactured as described herein or byvarious processes known to be present in the chemical art (see also, WO96/16080). For example, compounds of Group I may be synthesizedaccording to the schemes set forth in FIGS. 1-2 (1,3,4 oxadiazoles) andFIGS. 3-4 (1,2,4 oxadiazoles). FIGS. 5-7 describe the synthesis ofcompounds of Group II. FIGS. 8-9 describe the synthesis of compounds ofGroup III; FIG. 10 describes synthesis of Group IV compounds. Theseveral classes of Group V compounds are described in FIGS. 11-22.

Alternatively, the compounds of the present invention may be prepared asdescribed in FIG. 39. The 2-substituted 1,3,4-oxadiazole (3) may beprepared via formation of the acid chloride from an acid (1) utilizing,for example, thionyl chloride or oxalyl chloride, followed by treatmentwith hydrazine in a suitable solvent to yield the hydrazide (2).Reaction of (2) with triethyl orthoformate or trimethyl orthoformate andTsOH gives the requisite 2-substituted 1,3,4-oxadiazole (3).

Formation of the compound (3') utilizing standard conditions (ie.butyllithium at low temperature in a polar aprotic solvent, and further,if desired, reacting with MgBr-OEt₂) followed by addition of thealdehyde (4) yields the alcohol (5).

Deprotection of the protected amine of (5) using hydrochloric acid indioxane gives the amino hydrochloride (6) which is then coupled to theacid (7) by methods available to one skilled in the art to giveintermediate (8). Oxidation using Dess-Martin's Periodinane or othermethods as described in Oxidation in Organic Chemistry by MilosHudlicky, ACS Monograph 186 (1990) yields the ketone (9).

The final step requires removal of the protecting group from the amine.This may be carried out by a number of methods. For example, one mayutilize aluminum chloride, anisole and nitromethane in a suitablesolvent such as dichloromethane to give the final compound (10).Compound (10) can then be treated with an electrophile (e.g.,methanesulfonyl chloride) with added base to give (14).

The aldehyde (4) may be prepared via either of three methods described.The Weinreb amide (12) is prepared from the amino acid (11) which issubsequently reduced to the aldehyde using diisobutylalluminum hydride(DIBAL). Alternatively, one may generate the ester of the amino acid(13) followed by reduction with DIBAL to afford the aldehyde (4).Further, one may generate the alcohol (13-1) followed by oxidation withSO₃ -Py in DMSO.

The activity of the compounds is presented in FIGS. 23-38 as K_(i)values (nM). K_(i) values were determined, unless otherwise indicated,essentially as described in WO 96/16080, incorporated herein byreference.

Although the compounds described herein and/or their its salts may beadministered as the pure chemicals, it is preferable to present theactive ingredient as a pharmaceutical composition. The invention thusfurther provides the use of a pharmaceutical composition comprising oneor more compounds and/or a pharmaceutically acceptable salt thereof,together with one or more pharmaceutically acceptable carriers thereofand, optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be `acceptable` in the sense of being compatible withthe other ingredients of the composition and not deleterious to therecipient thereof.

Pharmaceutical compositions include those suitable for oral orparenteral (including intramuscular, subcutaneous and intravenous)administration. The compositions may, where appropriate, be convenientlypresented in discrete unit dosage forms and may be prepared by any ofthe methods well known in the art of pharmacy. Such methods include thestep of bringing into association the active compound with liquidcarriers, solid matrices, semi-solid carriers, finely divided solidcarriers or combination thereof, and then, if necessary, shaping theproduct into the desired delivery system.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. Tablets and capsules for oraladministration may contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets may be coated according to methods well known in the art., e.g.,with enteric coatings.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, emulsifying agents, non-aqueousvehicles (which may include edible oils), or preservative.

The compounds may also be formulated for parenteral administration(e.g., by injection, for example, bolus injection or continuousinfusion) and may be presented in unit dose form in ampules, pre-filledsyringes, small bolus infusion containers or in multi-does containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be in powderform, obtained by aseptic isolation of sterile solid or bylyophilization from solution, for constitution with a suitable vehicle,e.g., sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds may beformulated as ointments, creams or lotions, or as the active ingredientof a transdermal patch. Suitable transdermal delivery systems aredisclosed, for example, in Fisher et al. (U.S. Pat. No. 4,788,603) orBawas et al. (U.S. Pat. Nos. 4,931,279, 4,668,504 and 4,713,224).Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The active ingredient can also be delivered viaiontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122, 4383,529,or 4,051,842.

Compositions suitable for topical administration in the mouth includeunit dosage forms such as lozenges comprising active ingredient in aflavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

When desired, the above-described compositions can be adapted to providesustained release of the active ingredient employed, e.g., bycombination thereof with certain hydrophilic polymer matrices, e.g.,comprising natural gels, synthetic polymer gels or mixtures thereof.

The pharmaceutical compositions according to the invention may alsocontain other adjuvants such as flavorings, coloring, antimicrobialagents, or preservatives.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg/day, e.g., from about 1 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 0.5 to 1000 mg, conveniently 5 to 750 mg, mostconveniently, 10 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, more preferably, about 1 to 50 μM, most preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 0.5-500 mgof the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

The following examples are given to illustrate the invention and are notintended to be inclusive in any manner:

EXAMPLES

The following abbreviations are used below: TFA--trifluoroacetic acid;HOBT--hydroxybenzotriazole; DIEA--diisopropylethylamine;NMM--4-methylmorpholine; DMF--N,N-dimethylformamide; TEA--triethylamine;EDCI--1-(3-dimethylaminopropyl-3-ethylcarbodiimide;BOPCI--bis(2-oxo-3-oxazolidinyl)phosphinic chloride; FMOC--9-fluorenylmethoxycarbonyl; BTD--bicyclic turned dipeptide (see, e.g.,Tetrathedron, 49:3577-3592 (1993)); THF--tetrahydrofuran

Example 1 (CE-2072)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

To a mixture containing 0.79 g (5.94 mmol) of N-chlorosuccinimide in 40mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.65 mL (8.85 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing(benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamide (0.90 g,1.49 mmol) in 17 mL of anhydrous toluene. The reaction was allowed tostir for 2 hours at -25° C. followed by the addition of 1.0 mL (7.17mmol) of triethylamine. The cold bath was removed and the mixtureallowed to warm to room temperature and maintained for 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered and thesolvent removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel with 70% ethyl acetate/hexane togive 0.90 g of material which was further purified via preparative HPLCto afford 665 mg (73.9%) of the title compound as a white solid. FAB MS[M+H] m/z; Calcd: 604, Found 604.

The intermediate(benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamidewas prepared as follows:

a. 3-(S)-Amino-2-(R,S)-hydroxy-4-methyl pentanoic acid.

To a solution containing3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile (seeexample 1 of WO 96/16080) (15.2 g, 50.0 mmol) in 183 mL of dioxane wasadded 183 mL of concentrated hydrochloric acid and 7.45 mL of anisole.The reaction mixture was heated to reflux overnight. The hydrolysisreaction was allowed to cool to room temperature and then concentratedin vacuo. The resulting aqueous solution was extracted with ether (2×).The aqueous phase was placed on a Dowex 50X8-100 column (H⁺ form,preeluted with deionized water to pH=7). The column was eluted with 2.0N ammonium hydroxide and the pure fractions concentrated to afford 5.53g (75%) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid as a paleyellow solid. FAB MS [M+H] m/z; Calcd: 148, Found: 148.

b. 3-(S)-[(Benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoicacid.

To a solution under an atmosphere of nitrogen containing 1.0 g (6.8mmol) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5 mL of1 N NaOH and 10 mL of dioxane was added 1.43 g (8.4 mmol) of benzylchloroformate. The pH was maintained above pH 8 with 1 N NaOH as needed.The reaction mixture was allowed to stir at room temperature overnight.The reaction was diluted with water and washed with ether. The aqueouslayer was acidified with 1 N HCl to pH=2 and extracted with ether (2×).The combined organic layers were dried over magnesium sulfate, filteredand evaporated in vacuo to afford 1.75 g (92%) of3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acidas a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 282, Found: 282.

c. 3-(S)-[(Benzyloxylcarbonyl)amino]-2-(R,S)-acetoxy-4-methyl pentanoicacid.

To a solution of3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid(1.70 g, 6.04 mmol) and pyridine (4.9 mL) was added acetic anhydride(5.7 mL, 6.17 g, 60.4 mmol) dropwise at room temperature. The reactionwas allowed to stir overnight and was diluted with ethyl acetate andwashed with water (2×). The organic layer was dried over magnesiumsulfate, filtered and evaporated in vacuo to give a thick oil. Theresidue was purified by column chromatography on silica gel with 15%methanol/dichloromethane to afford 1.56 g (80%) of3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methyl pentanoic acidas a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 324, Found: 324.

d.1-[(3-Methylphenylacetyl)-2-(2-(R,S)-acetoxy)-3-(S)-[(benzyloxycarbonyl)amino]-4-methylpentanoyl]hydrazine.

To a solution containing3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methylpentanoic acid(2.3 g, 7.11 mmol) in 40 mL of DMF under a nitrogen atmosphere at 0° C.was added 1.31 g (9.69 mmol) of HOBT and 1.36 g (7.09 mmol) of EDCI.After stirring for 30 minutes, 1.20 g (7.31 mmol) of 3-methylphenylacetic hydrazide (prepared analogously to the monoacid hydrazides citedby Rabins et. al. (J. Org. Chem, 30:2486 (1965)) and 1.0 mL (9.10 mmol)of NMM were added. The reaction was allowed to warm to room temperatureand stir overnight. The reaction was diluted with ethyl acetate andwashed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate,brine and water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel with 10% methanol/dichloromethaneto afford 2.31 g (89.0%) of the title compound as a white solid. FAB MS[M+H] m/z; Calcd: 470, Found: 470.

e.1-[2-((5-(3-methylphenyl))-1,3,4-oxadiazolyl)]-1-acetoxy-2-(S)-[(benzyloxycarbonyl)amino]amino]-3-methylbutane.

A solution containing 2.31 g (4.92 mmol) of1-[(3-methylphenylacetyl)-2-(2-(R,S)-acetoxy)-3-(S)-[(benzyloxycarbonyl)amino]-4-methylpentanoyl]hydrazine in 25 mL of pyridine and 1.88 g (9.86 mmol) oftoluene sulfonyl chloride was heated at reflux under a nitrogenatmosphere for 72 hours. The solvent was removed under reduced pressureand the residue dissolved in ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel with 5% ethyl acetate/hexane to afford 1.41g (63.5%) of the title compound. FAB MS [M+H] m/z; Calcd: 452, Found:452.

f.1-[2-(5-[3-Methylbenzyl]-1,3,4-oxadiazolyl)]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-ol.

A solution containing 1.80 g (3.99 mmol) of1-[2-(5-[3-methylbenzyl]-1,3,4-oxadiazolyl)]-1-acetoxy-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutaneand 0.72 g (5.21 mmol) of potassium carbonate in 30 mL of methanol and 8mL of water was allowed to stir at room temperature for 30 minutes. Thesolvent was removed under reduced pressure and the residue dissolved inethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel with 50%ethyl acetate/hexane to afford 1.46 g (89.3%) of the title compound. FABMS [M+H] m/z; Calcd: 410, Found: 410.

g.1-[2-(5-[3-Methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-Amino-3-methylbutan-1-olhydrochloride.

To a solution containing 1.31 g (3.20 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-olin 25 mL of trifluoroacetic acid under a nitrogen atmosphere at 0° C.was added 0.43 mL (3.94 mmol) of thioanisole. The reaction was allowedto warm to room temperature overnight. The solvent was removed underreduced pressure and the residue dissolved in ether and cooled to -78°C. under a nitrogen atmosphere. To this solution was added 3 mL (3 mmol)of 1 N hydrochloric acid in ether. The resulting white solid was allowedto settle and the ether decanted. Additional ether was added anddecanted (3×). The solid was dried under vacuum to afford 0.92 g (92.2%)of the title compound. FAB MS [M+H) m/z; Calcd: 276, Found: 276.

h.(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl/hydroxylmethyl)-2-(S)-methylpropyl]-L-prolinamide.

To a solution containing 1.30 g (3.38 mmol) of Cbz-Val-Pro-OH in 25 mLof anhydrous dichloromethane under a nitrogen atmosphere at 0° C. wasadded 0.90 g (3.54 mmol) of BOPC1 and 0.60 g (3.44 mmol) of DIEA. Afterstirring for 30 minutes, 0.90 g (2.89 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride in 15 mL of dichloromethane and 0.6 mL (3.94mmol) of DIEA was added. The reaction was allowed to stir at 0° C.overnight. The reaction was diluted with dichloromethane and washed witha saturated sodium bicarbonate solution. The organic phase was driedover magnesium sulfate, filtered and evaporated. The residue waspurified by column chromatography on silica gel with 5%methanol/dichloromethane to afford 1.0 g (57.3%) of the title compoundas a tan solid. FAB MS [M+H] m/z; Calcd: 606, Found: 606.

Example 2(CE-2074)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(methyl)-1,3,4-oxadiazoly]carbony)]-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 514, Found: 514.Example 3(CE-2075)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-trifluoromethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 658, Found: 658.Example 4(CE-2100)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(4-Dimethylaminobenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 633, Found: 633.Example 5(CE-2124)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(1-napthylenyl)-1,3,4-xadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 640, Found: 640.Example 6(CE-2177)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 634, Found: 634.Example 7(CE-2178)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 634, Found: 634. Example 8(CE-2052)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-dimethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:618, Found: 618. Example 9(CE-2053)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-dimethoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 650, Found: 650. Example 10(CE-2054)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-ditrifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 726, Found: 726. Example 11(CE-2055)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 604, Found: 604. Example 12(CE-2057)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-biphenylmethine)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 666, Found: 666. Example 13(CE-2058)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(4-phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 666, Found: 666. Example 14(CE-2062)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-phenylbenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Preparedsimilar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 666,Found: 666. Example 15(CE-2066)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-phenoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 682, Found: 682. Example 16(CE-2069)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-cyclohexylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 596, Found: 596. Example 17(CE-2073)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(α,α-dimethyl-3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:686, Found: 686. Example 18(CE-2077)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(1-napthylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 640, Found: 640. Example 19(CE-2078)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-pyridylmethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 591, Found: 591. Example 20(CE-2096)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-diphenylbenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar toExample 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 742, Found: 742.Example 21(CE-2115)(Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(4-dimethylaminobenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 633, Found: 633. Example 22(CE-2089)2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamide.

To a mixture containing 1.15 g (8.60 mmol) of N-chlorosuccinimide in 43mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.95 mL (12.9 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamide(1.52 g, 2.15 mmol) in 15 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at -25° C. followed by the addition of 1.2mL (8.60 mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature over 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution of 2 to 10%methanol/dichloromethane to afford 1.19 g of material which was furtherpurified via preparative HPLC to afford 629 mg (41%) of the titlecompound as a white solid. FAB MS [M+H] m/z; Calcd: 707, Found: 707.

The intermediate2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamidewas prepared as follows: to a solution containing 1.35 g (3.7 mmol) of1-[3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride and[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]aceticacid (J. Med. Chem. 38:98-108 (1995)) in 10 mL of anhydrous DMF wasadded 1.0 mL (7.44 mmol) of TEA and 0.76 g (4.94 mmol) of HOBT. Themixture was cooled to 0° C. and 0.95 g (4.94 mmol) of EDC was added andthe reaction mixture was allowed to stir overnight. An additional 1.0 mL(7.44 mmol) of TEA was added and the reaction again allowed to stirovernight. The reaction was diluted with dichloromethane and washed witha saturated ammonium chloride solution (2×) and water. The organic phasewas dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel with 2% methanol/dichloromethane to afford 1.52 g (87%) of the titlecompound. FAB MS [M+H] m/z; Calcd: 709, Found: 709.

Example 23 (CE-2090)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-]1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 0.41 g (0.56 mmol) of 2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-1,2,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamidein 4 mL of trifluoracetic acid at room temperature under a nitrogenatmosphere was added 87 mg (0.70 mmol) of thioanisole. The reactionmixture was allowed to stir for 3 days and concentrated in vacuo. Theresidue was purified via preparative HPLC to afford 269 mg (47%) of thetitle compound as a white solid. FAB MS [M+H] m/z; Calcd: 573, Found:573.

Example 24 (CE-2095)2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamide.

To a mixture containing 0.83 g (6.23 mmol) of N-chlorosuccinimide in 32mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.7 mL (9.35 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamide(1.02 g, 1.56 mmol) in 12 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at -25° C. followed by the addition of 0.9mL (6.23 mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature over 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered andevaporated. The residue was purified by column chromatography on silicagel using 1% methanol/dichloromethane to afford 1.37 g of material whichwas further purified via preparative HPLC to give 368 mg (36%) of thetitle compound as a white solid. FAB MS [M+H] m/z; Calcd: 653, Found:653.

The intermediate2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamidewas prepared as follows: to a solution containing 1.35 g (3.7 mmol) of1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methyl butanehydrochloride and[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]aceticacid (J. Med. Chem., 38:98-108 (1995)) in 10 mL of anhydrous DMF wasadded 0.73 mL (6.6 mmol) of NMM and 0.46 g (3.0 mmol) of HOBT. Themixture was cooled to 0° C. and 0.50 g (2.6 mmol) of EDCI was added andthe reaction mixture was allowed to stir for 2 days. The reaction wasdiluted with dichloromethane and washed with a saturated ammoniumchloride solution (2×) and water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using agradient elution of 2 to 5% methanol/dichloromethane to afford 1.02 g(77%) of the title compound. FAB MS [M+H] m/z; Calcd: 655, Found: 655.

Example 25 (CE-2101)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 0.219 g (0.335 mmol) of2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropylyl]acetamidein 3 mL of trifluoroacetic acid at room temperature under a nitrogenatmosphere was added 0.05 mL (0.402 mmol) of thioanisole. The reactionmixture was allowed to stir for 3 days and concentrated in vacuo. Theresidue was purified via preoperative HPLC to afford 187 mg (88%) of thetitle compound as a white solid. FAB MS [M+H} m/z; Calcd: 519, Found:519.

Example 26(CE-2164)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl-2-(S)-methylpropyl]amide.

To a mixture containing 1.97 g (14.7 mmol) of N-chlorosuccinimide on 60mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added1.54 mL (21.0 mmol) of dimethyl sulfide. The mixture was allowed to stirfor 1 hr. The reaction was cooled to -25° C. using a carbontetrachloride/dry ice bath, followed by the dropwise addition of asolution contain (0.90 g, 1.49 mmol) of(pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-2-(S)-methylpropyl]amidein 30 mL of anhydrous toluene. The reaction was allowed to stir for 1hour at -25° C. followed by the addition of 2.16 mL (15.5 mmol) oftriethylamine. The cold bath was removed and the mixture allowed to warmto room temperature over 20 minutes. The reaction mixture was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate, filtered and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel withethyl acetate/hexane (4:1). The material was further purified viapreparative HPLC to afford 1.20 g (63.4%) of the title compound as awhite solid. FAB MS [M+H] m/z; Calcd: 514, Found: 514.

The intermediate(pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-2-(S)-methylpropyl]amidewas prepared by the following method:

a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester.

To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylicacid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphereat 0° C. was added 6.96 g (27.0 mmol) of BOPC1 and 14.1 mL (81.0 mmol)of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) ofN-(benzyl)gylcine-t-butyl ester was added and the reaction allowed towarm to room temperature overnight. The reaction was diluted with ethylacetate and washed with a 5% potassium hydrogensulfate, saturated sodiumbicarbonate solution and brine. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using agradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g(34.4%) of the title compound as a white solid. FAB MS [M+H] m/z Calcd:315, Found: 315.

b. (Pyrrole-2-carbonyl)-N-(benzyl)glycine.

To a solution containing 2.85 g (9.01 mmol) of(Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL ofanhydrous dichloromethane cooled to 0° C. was added 25 mL of TFAdropwise. After 90 minutes an additional 25 mL of TFA was added andallowed to stir for 30 minutes. The mixture was evaporated in vacuo toafford 2.19 g of (Pyrole-2-carbonyl)-N-(benzyl)glycine as a tan solid.FAB MS [M+H] m/z; Calcd. 259, Found 259.

c.(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-(S)-2-methylpropyl]amide.

To a solution containing 1.90 g (7.35 mmol) of(Pyrrole-2-carbonyl)-N-(benzyl)glycine in 75 mL of anhydrous DMF wasadded 2.4 mL (22.1 mmol) of NMM and 1.29 g (9.56 mmol) of HOBT. Themixture was cooled to 0° C. and 1.69 g (8.82 mmol) of EDCI was added andthe reaction mixture was allowed to stir. After 30 minutes 2.17 g (6.99mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride in 25 mL of anhydrous DMF was added and themixture was allowed to warm to room temperature overnight. The reactionwas diluted with ethyl acetate and washed with 5% potassium hydrogensulfate and water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a gradient elution of 20 to80% ethyl acetate/hexane to afford 2.02 g (56%) of the title compound.FAB MS [M+H] m/z Calcd: 516, Found: 516.

Example 27(CE-2097)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)]-1,2,4-oxadiazolyl]carbonyl)-(S)-methylpropyl]amidewas prepared in a similar manner to Example 25. FAB MS [M+H] m/z; Calcd:568, Found: 568. Example 28(CE-2130)(2S,5S)-5-Amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(R,S)-2-methylpropyl]amide.

To a solution containing 0.93 g (1.28 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4, 5,6,7-hexahydroazepino [3,2,1]indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amidein 4.5 mL of anhydrous DMF under an atmosphere of nitrogen was added0.45 mL of diethylamine. After stirring at room temperature for 15 minthe mixture was concentrated under high vacuum. The residue was purifiedvia preparative HPLC to afford 0.57 g (72%) of the title compound as awhite solid. FAB MS [M+H] m/z; Calcd: 502, Found 502.

The intermediate(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amidewas prepared as follows:

a. (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]amide.

To a solution containing 1.25 g (2.67 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino [3,2,1]indole-4-one-carboxylic acid in 200 mL of anhydrous dichloromethane and1 mL of anhydrous DMF under a nitrogen atmosphere at 0° C. was added0.71 g (2.80 mmol) of BOPC1 and 0.6 mL (3.45 mmol) of DIEA. Afterstirring for 1 hr 1.14 g (3.66 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of anhydous dichloromethane was added and thereaction mixture allowed to stir at 4° C. overnight. The reaction wasdiluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatograph on silica gelusing 3% methanol/dichloromethane to afford 1.30 g (67%) of the titlecompound as tan solid.

b. (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)]-(S)-2-methylpropyl]amide.

To a mixture containing 0.95 g (7.16 mmol) of N-chlorosuccinimide in 150mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.79 mL (10.7 mmol) of dimethyl sulfide. The mixture was allowed to stirfor 30 minutes. The reaction was cooled to -25° C. using a carbontetrachloride/dry ice bath, followed by the dropwise addition of asolution containing 1.30 g (1.79 mmol) of (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-(S)-2-methylpropyl]amidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 1.17 mL (8.4 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 30 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. The residue was filtered, concentratedunder reduced pressure and purified by column chromatography on silicagel with 10% ethyl acetate/hexane to give 0.93 g (72%) as a tan foam.

Example 29 (CE-2126)BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.

To a solution containing 0.41 g (0.59 mmol) ofFMOC-BTD-[l-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazole]carbonyl)-2-(S)-methylpropyl]amidein 4.5 mL of anhydrous DMF under an atmosphere of nitrogen was added 0.5mL of diethylamine. After stirring at room temperature for 30 min themixture concentrated under high vaccum. The residue was purified viapreparative HPLC to afford 0.23 g (66%) of the title compound as a whitesolid. FAB MS [M+H] m/z; Calcd: 472, Found 472.

The intermediateFmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amidewas prepared as follows:

a. (2S,5S)-Fmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amide.

To a solution containing 1.25 g (2.85 mmol) of FMOC-BTD in 80 mL ofanhydrous dichloromethane and 2.5 mL of anhydrous DMF under a nitrogenatmosphere at 0° C. was added 0.76 g (2.99 mmol) of BOPC1 and 0.6 mL(3.45 mmol) of DIEA. After stirring for 30 minutes and 1.14 g (3.66mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride and 0.6 mL of DIEA in 10 mL of anhydrous dichloromethanewas added and the reaction mixture allowed to stir at 0° C. overnight.The reaction was diluted with dichloromethane and washed with water. Theorganic phase was dried over magnesium sulfate, filtered and evaporatedunder reduced presure. The residue was purified by column chromatographyon silica gel using 3% methanol/dichloromethane to afford 1.13 g (55%)of the title compound as a tan foam.

b. Fmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1, 3,4-oxadiazolyl]carbonyl)]-2-(S)-methylpropyl]amide.

To a mixture containing 0.81 g (6.09 mmol) of N-chlorosuccinimide in 110mL of 1:1 anhydrous dichloromethane/toluene at 0° C. under a nitrogenatmosphere was added 0.67 mL (9.1 mmol) of dimethyl sulfide. The mixturewas allowed to stir for 30 minutes. The reaction was cooled to -25° C.using a carbon tetrachloride/dry ice bath, followed by the dropwiseaddition of a solution containing 1.06 g (1.52 mmol) ofFmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 1.0 mL (7.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 40 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. The resulting mixture was filtered,concentrated under reduced pressure and purified by columnchromatography on silica gel with 70% ethyl acetate/hexane to give 0.53g of the product as a yellow oil. The material was further purified bypreparative HPLC to afford 0.41 g (38.8%) of the title compound as awhite solid.

Example 30(CE-2134)(R,S)-3-Amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 0.93 g (1.19 mmol)of(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide in 6.0 mL ofanhydrous DMF under an atmosphere of nitrogen was added 0.45 mL ofdiethylamine. After stirring at room temperature for 2.5 hr the mixturewas concentrated under high vaccum. The residue was purified viapreparative HPLC to afford 0.030 g (4.5%) of the title compound as awhite solid. FAB MS [M+H] m/z; Calcd: 565, Found 565.

The intermediate(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a.(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[]-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 0.75 g (1.41 mmol) of(R,S)-FMOC-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1,4,-benzodiazepinein 30 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0°C. was added 0.36 g (1.41 mmol) of BOPC1 and 0.25 mL (1.41 mmol) ofDIEA. After stirring for 1 hr 0.48 g (1.55 mmol) of1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride and 0.49 mL (2.82 mmol) of DIEA in 10 mL ofanhydous dichloromethane was added and the reaction mixture allowed tostir at 4° C. overnight. The reaction was diluted with ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a gradient of 2 to 6%methanol/dichloromethane to afford 1.00 g (89%) of the title compound asa yellow solid.

b.(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 0.71 g (7.6 mmol) of N-chlorosuccinimide in 40mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.84 mL (11.4 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath followed by the dropwiseaddition of a solution containing 1.50 g (1.90 mmol) of(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 1.0 mL (7.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 1 hour. The reaction mixture was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate. The residue was filtered, concentrated underreduced pressure to afford 0.94 g (62%) of material which was usedwithout further purification. FAB MS [M+H] m/z; Calcd: 787, Found: 787.

Example 31(CE-2145)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.

To a mixture containing 0.48 g (3.67 mmol) of N-chlorosuccinimide in 30mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.40 mL (5.41 mmol) of dimethyl sulfide. After stirring for 1 hr thereaction mixture was cooled to -25° C. using a carbon tetrachloride/dryice bath followed by the dropwise addition of a solution containing 0.95g (1.90 mmol) of(benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amidein 20 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at -25° C. followed by the addition of 0.50 mL (3.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature. The reaction mixture was diluted withdichloromethane and washed with 1 N HCl (2×), saturated sodiumbicarbonate (2×) and water. The organic phase was dried over magnesiumsulfate. The mixture was filtered and concentrated under reducedpressure to afford 0.61 g. The residue was purified by columnchromatography on silica gel with 50% ethyl acetate/hexane to afford0.27 g of material which was further purified via preparative HPLC toafford 196 mg (33.4%) of the title compound as a white solid. FAB MS[M+H] m/z Calcd: 652, Found 652.

The intermediate(benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amidewas prepared by the following procedures:

a. 2-L-Methyl (2,3-dihydroindole)carboxylate.

To a suspension containing 5.00 g (30.6 mmol) of2-L-(2,3-dihydroindole)carboxylic acid in 100 mL of anhydrous MeOHcooled to 0° C. was added a slow stream of HCl gas over 20 minutes. Theresulting homogeneous solution was allowed to stir overnight warming toroom temperature. The mixture was evaporated and the residue wascrystallized from methanol/ether to afford, after drying, 5.58 g (85%)of 2-L-methyl (2,3-dihydroindole)carboxylate.

b. 2-Methyl[(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylate.

To a solution containing 3.00 g (14.0 mmol) of methyl(2,3-dihydroindole)-L-2-carboxylate in 60 mL of anhydrousdichloromethane, under a nitrogen atmosphere at 0° C., 7.15 g (28.8mmol) of BOPCl and 7.72 mL (70.2 mmol) of DIEA was added a solution of7.06 g (28.08 mmol) of Cbz-Val-OH in 40 mL of anhydrous dichloromethaneand 3 mL of DMF. After stirring for 3 days at 5° C. the mixture wasdiluted with ethyl acetate and washed with 1 N HCl (2×) and brine. Themixture was filtered and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using a gradient of9:1 to 1:1 hexane/ethyl acetate to afford 4.85 g (87%) of the titlecompound as a white foam.

c. 2-[(S)-1-(N-[Benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylic acid.

To a solution containing 4.85 g (12.17 mmol) of 2-methyl[(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylatein 45 mL of THF and 15 mL of MeOH at 0° C. was added 15.8 mL of 1 N LiOHdropwise. After 30 minutes 1 N HCl was added to pH 2 and the mixtureextracted with ethyl acetate (3×). The combined organic phases weredried over magnesium sulfate, filtered and evaporated under reducedpresure to afford 4.51 g (93%) of the title compound as a white solid.

d.(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amide.

To a solution containing 1.09 g (3.96 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-oland 1.31 g (3.3 mmol) of2-[(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylicacid in 30 mL of anhydrous dichloromethane was added 1.21 mL (6.93 mmol)of DIEA and 0.49 g (3.63 mmol) of HOBT. The mixture was cooled to 0° C.and 0.70 g (3.63 mmol) of EDCI was added and the reaction mixture wasallowed to stir overnight. An additional 1.0 mL (7.44 mmol) of TEA wasadded and the reaction again allowed to stir overnight. The reaction wasdiluted with dichloromethane and washed with 1 N HCl (2×), saturatedsodium bicarbonate (2×) and water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel with 80%ethyl acetate/hexane to afford 0.66 g (30%) of the title compound.

Example 32(CE-2125)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd:706, Found: 706. Example 33 (CE-2143)Acetyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd:515, Found: 515. Example 34 (CE-2165)N-Acetyl-2-(L)-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd:461; Found: 461. Example 35(CE-2104)(Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

To a mixture containing 0.69 g (5.17 mmol) of N-chlorosuccinimide in 60mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.60 mL (8.17 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the additionof a solution containing(morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S-)methylpropyl]-L-prolinamide (0.75 g, 1.28 mmol) in 10 mL of anhydrous toluene.The reaction was allowed to stir for 2 hours at -25° C. followed by theaddition of 1.1 mL (0.83 g, 7,89 mmol) of triethylamine. The cold bathwas removed and the reaction was allowed to warm to room temperatureover 20 minutes. The reaction was diluted with ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate andfiltered. The solvents were evaporated in vacuo and the residue purifiedby column chromatography, 70% ethyl acetate/hexane on silica gel. Finalpurification was performed by preparative HPLC to afford 405 mg (54.3%)of the title compound as a white solid. FAB MS [M+H] m/z; Calcd: 583,Found: 583.

The intermediate(Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyll)-2-(S)-methylpropyl]-L-prolinamidewas prepared as follows:

a. (Morpholino-N-carbonyl)-L-valyl-L-proline-O-t-butyl ester.

To a solution containing L-valyl-L-proline-O-t-butyl-ester (1.80 g, 5.87mmol) in 80 mL of anhydrous methylene chloride and 1.5 mL (13.64 mmol)of N-methyl morpholine under a nitrogen atmosphere at 0° C. was addedmorpholine carbonyl chloride dropwise. The mixture was allowed to warmto room temperature overnight. The reaction was diluted with methylenechloride and washed with water. The organic layer was dried overmagnesium sulfate, filtered and evaporated. The residue was purified bycolumn chromatography on silica gel with 10% methanol/dichloromethane toafford 1.98 g (88%) of the title compound as a white solid. FAB MS [M+H]m/z; Calcd: 384, Found 384.

b. (Morpholino-N-carbonyl)-L-valyl-L-proline.

To a solution containing(morpholino-N-carbonyl)-L-valyl-L-proline-O-t-butyl ester (2.0 g, 5.22mmol) in 80 mL of anhydrous methylene chloride under a nitrogenatmosphere at 0° C. was added trifluoroacetic acid (13 mL, 130 mmol).The mixture was allowed to warm to room temperature overnight and thesolvents were evaporated in vacuo to give 2.26 g of a viscous oil. Thematerial was used without further purification.

c.(Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamide.

To a solution containingn 0.95 g (2.90 mmol) of(morpholino-N-carbonyl)-L-valyl-Proline in 25 mL of anhydrousdichloromethane under a nitrogen atmosphere at 0° C. was added 0.80 g(3.14 mmol) of BOPCI and 1.5 mL (8.61 mmol) of DIEA. After 30 minutes,0.75 g (2.41 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 1.1 mL (6.31 mmol) of DIEAwere added. The reaction was allowed to stir at 0° C. overnight. Thereaction was diluted with dichloromethane and washed with a saturatedNaHCO₃ solution. The organic phase was dried over magnesium sulfate andfiltered. The mixture was concentrated in vacuo and the residue purifiedby column chromatography on silica gel using 6% methanol/dichloromethaneto afford 0.77 g (54.84%) of the title compound as a white solid. FAB MS[M+H] m/z; Calcd: 585, Found: 585.

Example 36 (CE-2079)3-(S)-(Benzyloxycarbonyl)amino)-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 2.37 g (17.75 mmol) of N-chlorosuccinimide in100 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 1.94 mL (2.64 mmol) of dimethyl sulfide. The reaction was cooledto -25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing 2.5 g (4.44 mmol) of3-(S)-[(benzyloxycarbonyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 20 mL of anhydrous toluene. Upon complete addition,the reaction was allowed to stir at -25° C. for 2 hours, followed by theaddition of 3.0 mL (21.52 mmol) of triethylamine. The cold bath wasremoved and the reaction warmed to room temperature and stirred for 30minutes. The reaction was diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent and column chromatography of the residue on silicagel with 5% methanol/dichloromethane afforded 1.8 g of a pale yellowsolid. Subsequent preparative HPLC gave 950 mg (38.1%) of the titlecompound as a white solid. FAB MS [M+H] m/z; Calcd: 562, Found: 562.

The intermediate3-(S)-[(benzyloxycarbonyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared as follows:

a. 3-(S)-[(Benzyloxycarbonyl)amino]-ε-lactam.

To a mixture containing 9.9 g (37.18 mmol) of Cbz-omithine in 150 mL ofacetonitrile under a nitrogen atmosphere was added 78 mL (369.70 mmol)of hexamethyldisilazane. The reaction was heated at reflux for 48 hours.The reaction mixture was cooled to room temperature and poured into 250mL of cold methanol. The solvent was removed under reduced pressure.Chloroform was added and the mixture filtered through a plug of celite.The filtrate was concentrated under reduced pressure and the residuedissolved in ethyl acetate. Hexane was added until the solution wasslightly turbid and then allowed to stand overnight. The resultant solidwas filtered and dried to afford 8.37 g (90.7%) of the title compound.

b. N-[3-(S)-(Benzyloxycarbonyl)amino]-ε-lactam-t-butyl acetate.

To a solution containing 1.0 g (4.03 mmol) of3-(S)-[(benzyloxylcarbonyl)amino]-ε-lactam in 20 mL of anhydrous DMFunder a nitrogen atmosphere was added 1.50 mL (10.16 mmol) ofbromo-t-butyl acetate and 1.17 g (5.05 mmol) of silver oxide. Thereaction was heated to 45° C. for 5 hours, diluted with acetonitrile andfiltered through a pad of celite. The filtrate was concentrated underreduced pressure and the residue dissolved in ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate.Filtration, removal of solvent and column chromatography of the residueon silica get with 60% ethyl acetate/hexane afforded 1.18 g (80.79%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 363, Found: 363.

c. N-[3-(S)-(Benzyloxycarbonyl)amino)-ε-lactam-carboxymethane.

To a solution containing 0.55 g (1.52 mmol) of N-[3-(S)-(Benzyloxycarbonyl)amino]-ε-lactam-t-butyl acetate in 20 mL (15.58 mmol) oftrifluoroacetic acid. The reaction was allowed to warm to roomtemperature overnight. The solvent was removed under reduced pressure.The residue was dissolved in ether acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration and removalof solvent afforded 0.50 of the title compound. FAB MS [M+H] m/z; Calcd:307, Found: 307.

d. 3-(S)-[Benzyloxycarbonyl)amino)-ε-lactam-N-[]-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 2.72 g (8.88 mmol) ofN-[3-(S)-(Benzyloxycarbonyl) amino]-ε-lactam-carboxymethane in 80 mL ofdichloromethane under a nitrogen atmosphere at 0° C. was added 2.37 g(9.31 mmol) of BOPCI and 1.60 mL (9.91 mmol) of DIEA. The reacton wasallowed to stir at 0° C. for 30 minutes followed by the addition of 2.37g (7.60 mmol) of1-[3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3methylbutan-1-ol hydrochloride in 20 mL of dichloromethane and 1.60 mL (9.19mmol) of DIEA. The reaction was allowed to stir at 0° C. overnight. Thereaction was diluted with dichloromethane and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent and column chromatography of the residue on silica get with 10%methanol/dichloromethane afforded 2.58 g (50.23%) of the title compound.FAB MS [M+H] m/z; Calcd: 564, Found: 564.

Example 37 (CE-2080)3-(S-(Amino)-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidetrifluoroacetic acid salt.

This compound was prepared via deprotection of3-(S)-[benzyloxycarbonyl)amino)-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide under standard conditions to one skilled in the art toafford the title compound. FAB MS [M+H] m/z; Calcd: 428, Found: 428.

Example 38 (CE-2091) 3-(S)-[(4-Morpholinocarbonyl-butanoyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.

To a solution containing 0.089 g (0.475 mmol) of 4-morpholino carbonylbutanoic acid in 10 mL of dichloromethane under a nitrogen atmosphere at0° C. was added 0.127 g (0.498 mmol) of BOPCI and 0.09 mL (0.492 mmol)of DIEA. The reaction was allowed to stir for 30 minutes followed by theadditin of 0.22 g (0.406 mmol) of3-(S)-amino-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methyl propyl]acetamidetrifluoroacetic acid salt. The reaction was allowed to stir at 0° C.overnight. The reaction was diluted with dichloromethane and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent and purification via preparative HPLC afforded 0.044g (18%) of the title compound. FAB MS [M+H] m/z; Calcd: 597, Found: 597.

Example 39 (CE-2087)6-[4-Fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 0.70 g (5.24 mmol) and N-chlorosuccinimide in 30mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.60 mL (8.17 mmol) of dimethyl, sulfide. The reaction was cooled to-25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing 0.67 g (1.32 mmol) of6-[4-fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in15 mL of anhydrous toluene. Upon complete addition, the reaction wasallowed to stir at -25° C. for 2 hours followed by the addition of 0.90mL (6.46 mmol) of triethylamine. The cold bath was removed and thereaction allowed to warm to room temperature and maintained for 20 min.The reaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent under reduced pressure and column chromotography of the residueon silica gel with 10% methanol/dichloromethane afforded 0.61 g of apale yellow solid. Subsequent preparative HPLC gave 338 mg (50.5%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 507, Found: 507.

The intermediate6-[4-fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a. 6-[4-Fluorophenyl]-6-carboxymethylene-2-piperidinone.

To a solution containing 2.15 g (8.11 mmol) of6-[4-fluorophenyl]-1-carbomethoxymethylene-2-piperidinone, prepared in asimilar fashion to that reported by Compernolle (Tetrahedron, 49:3193(1993)) in 70 mL of methanol and 20 mL of water under a nitrogenatmosphere was added 0.55 g (13.11 mmol) of lithium hydroxide. Thereaction was allowed to stir at room temperature for 2 hours. Thesolvent was removed under reduced pressure. The residue was diluted withwater and washed with ethyl acetate. The aqueous phase was acidifiedwith 1 N hydrochloric acid and extracted with ethyl acetate. The organicphase was dried over magnesium sulfate. Filtration and removal ofsolvent afforded 2.0 g (98.2%) of the title compound. FAB MS [M+H] m/z;Calcd: 252, Found: 252.

b.6-[4-Fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 1.04 g (4.14 mmol) of6-[4-fluorophenyl]-6-carboxymethylene-2-piperidinone in 25 mL ofanhydrous dichloromethane under a nitrogen atmosphere at 0° C. was added1.10 g (4.32 mmol) of BOPCI and 0.80 mL (4.59 mmol) of DIEA. Afterstirring for 30 minutes, a solution containing 1.1 g (3.53 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 1.10 mL (6.31 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight. The reactionwas diluted with dichloromethane and washed with a saturated sodiumbicarbonate solution. The organic phase was dried over magnesiumsulfate. Filtration, removal of solvent under reduced pressure andcolumn chromotography of the residue on silica gel with 10%methanol/dichloromethane afforded 736 mg (41.0%) of the title compound.FAB MS [M+H] m/z; Calcd: 509, Found: 509.

Example 40 (CE-2121)2-[2-(R,S)-Phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 2.05 g (15.38 mmol) of N-chlorosuccinimide in250 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 1.70 mL (23.06 mmol) of dimethyl sulfide. The reaction was cooledto -25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of 1.90 g (3.84 mmol) of2-[2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 20 mL of anhydrous toluene dropwise. The reaction was allowed to stirat -25° C. for 2 hours, followed by the addition of 2.52 mL (18.07 mmol)of triethylamine. The cold bath was removed and the reaction allowed towarm to room temperature over 40 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent and columnchromatography of the residue on silica gel with 60% ethylacetate/hexane afforded 1.10 g of a yellow oil. This was furtherpurified via preparative HPLC to give 0.45 g (24%) of the title compoundas an off-white solid. FAB MS [M+H] m/z; Calcd: 493, Found 493.

The intermediate2-[2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methypropyl]acetamidewas prepared as follows: to a solution containing 1.78 g (7.51 mmol) of2-(2-phenyl-4-oxothiazolidin-3-yl) acetic acid, prepared according toHolmes (J. Org. Chem, 60:7328 (1995)), in 80 mL of dichloromethane undera nitrogen atmosphere at 0° C. was added 2.04 g (8.02 mmol) of BOPCI and1.35 mL (7.76 mmol) of DIEA. After stirring for 30 minutes, 2.0 g (6.41mmol) of1-[3-[5-(3-methylbenzyl)]-1,3,4-oxadiazolyl]-2-(S)-amino-3-methyl-butan-1-olhydrochloride in 50 mL of dichloromethane and 1.35 mL (7.76 mmol) ofDIEA was added. The reaction was allowed to stir at 0° C. overnight. Thereaction mixture was diluted with dichloromethane and washed with water.The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Column chromatography of theresidue on silica gel with 4% methanol/dichloromethane afforded 2.30 gof a yellow foam. Subsequent preparative HPLC gave 1.9 g of the titlecompound. FAB MS [M+H] m/z; Calcd: 495, Found: 495.

Example 41 (CE-2122)2-[2-(R,S)-Benzyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner as in Example 39. FAB MS[M+H] m/z; Calcd: 507, Found: 507. Example 42 (CE-2136)2-[(2-(R,S)-Benzyl-4-oxothiazolidin-3-yl oxide]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(R,S,)-methylpropyl] acetamide.

To a solution containing 1.31 g (2.59 mmol) of2-[2-(R,S)-benzyl-4-oxothiazolidin-3-yl)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methyl propyl]-acetamide in 15 mL of methanol under anitrogen atmosphere was added 0.51 mL (5.17 mmol) of 30% hydrogenperoxide. The reaction was allowed to stir at room temperature overnightand then partitioned between brine and dichloromethane. The organicphase was dried over magnesium sulfate. Filtration, removal of solventunder reduced pressure and column chromatography of the residue onsilica gel with 85% ethyl acetate/hexane afforded 0.73 g of a tan oil.Subsequent preparative HPLC gave 0.54 g (48%) of the title compound. FABMS [M+H] m/z; Calcd: 523, Found 523.

Example 43 (CE-2137) 2-[2-(R,S)-Benzyl-4-oxothiazolidin-3-yloxide]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S,)-methylpropyl] acetamide. Prepared in a similar manneras in Example 41. FAB MS [M+H] m/z; Calcd: 577, Found 577. Example 44(CE-2118)2-[2-(R,S)-Phenyl-4-oxometathiazan-3yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide. Prepared in a similar manner asin Example 39. FAB MS [M+H] m/z; Calcd: 507, Found: 507. Example 45(CE-2140)(1-Benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide.

To a mixture containing 1.70 g (2.74 mmol) of N-chlorosuccinimide in 75mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added1.70 mL (23.15 mmol) of dimethyl sulfide. The reaction was cooled to-25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of 1.90 g (3.27 mmol) of(1-Benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl] acetamide in 10 mL of toluene dropwise. The reaction was allowedto stir at -25° C. for 2 hours, followed by the addition of 3.20 mL(22.96 mmol) of triethylamine. The cold bath was removed and thereaction allowed to warm to room temperature and maintained for 15minutes. The reaction was diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate, filtered, andthe solvent removed under reduced pressure. The residue waschromatographed on silica gel with 5% methanol/dichloromethane to afford1.37 g of a brown oil. This was further purified via preparative HPLC togive 450 mg (40.1%) of the title compound. FAB MS [M+H]m/z; Calcd: 580,Found: 580.

The intermediate(1-benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a. 1-Benzoyl-3,8-quinazolinedione-2-t-butyl acetate.

To a solution containing 5.0 g (18.78 mmol) of1-Benzoyl-3,8-quinazolinidione prepared in a similar manner to thatreported by Melnyk et al. (Tetrahedron Lett., 37:4145 (1996)), in 100 mLof DMF under a nitrogen atmosphere was added 4.30 mL (29.12 mmol) ofbromo t-butylacetate and 5.4 g (23.30 mmol) of silver oxide. Thereaction was heated to 50° C. overnight, diluted with ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate.Filtration, removal of solvent under reduced pressure and columnchromatography of the residue on silica gel with 40% ethylacetate/hexane gave 5.25 g (73.49%) of product. FAB MS [M+Hl] m/z;Calcd: 381, Found: 381.

b. 1-Benzoyl-2-carboxymethylene-3,8-quinazolinedione.

To a solution containing 5.20 g (13.67 mmol) of1-benzoyl-3,8-quinazolinedione-2-t-butyl acetate in 300 mL ofdichloromethane under a nitrogen atmosphere at 0° C. was added 21.0 mL(211.44 mmol) of trifluroacetic acid. The reaction was allowed to warmto room temperature overnight. The solvent was removed under reducedpressure and the residue dissolved in ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent afforded 4.32 g (97.45%) of the title compound.FAB MS [M+H]m/z; Calcd: 325, Found: 325.

c.(1-Benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 1.80 g (5.55 mmol) of1-benzoyl-2-carboxymethylene-3,8-quinazolinedione in 100 mL of anhydrousdichloromethane and 5 mL of DMF under a nitrogen atmosphere at 0° C. wasadded 1.90 g (7.46 mmol) of BOPCI and 1.40 mL (8.05 mmol) of DIEA. Afterstirring for 30 minutes, a solution containing 1.70 g (5.45 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 20 mL of dichloromethane and 3.80 mL (21.84 mmol) ofDIEA was added. The reaction was allowed to stir at 0° C. overnight,diluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 10% methanol/dichloromethane afforded 1.93 g (60.9%) of the titlecompound. FAB MS[M+H]m/z; Calcd: 582, Found: 582.

Example 46(CE-2138)(1-Benzoyl-3,6-piperazinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide. Prepared in a similar manner asin Example 44. FAB MS [M+H]m/z; Calcd: 532, Found: 532. Example 47(CE-2147)(1-Phenyl-3,6-piperazinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide. Prepared in a similar manner asin Example 44. FAB MS [M+H]m/z; Calcd: 504, Found: 504. Example 48(CE-2148)(1-Phenyl-3,6-piperazinedione)-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide. Prepared in a similar manner asin Example 44. FAB MS [M+H] m/z; Calcd:558, Found: 558. Example 49(CE-2108)3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 0.16 g (1.18 mmol) of N-chlorosuccinimide in 20mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.13 mL (1.77 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath followed by the addition ofa solution containing 0.18 g (0.30 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-Oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 20 mL of methylene chloride dropwise. The reaction was allowed tostir at -25° C. for 2 hours, followed by the addition of 0.19 mL (1.38mmol) of triethylamine. The cold bath was removed and the reaction wasallowed to warm to room temperature and maintained for 30 minutes. Thereaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent under reduced pressure and column chromatography of the residueon silica gel with 3% methanol/dichloromethane afforded 0.23 g of anoil. Further purification via preparative HPLC gave 100 mg of the titlecompound.

FAB MS [M+H} m/z; Calcd: 608, Found: 608

The intermediate3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethly)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a. 3-[(Benzyloxycarbonyl)amino]-quinoline-2-one.

To a solution containing 0.5 g (3.10 mmol) of3-amino-quinoline-2-(1H)-one described by Anderson, et. al. (J.Heterocyclic Chem., 30:1533 (1993)) in 40 mL of dioxane under a nitrogenatmosphere was added 0.14 g (3.4 mmol) of sodium hydroxide in 14 mL ofwater. The reaction mixture was cooled to 0° C., followed by theaddition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of thereaction was maintained above 8.0 with additional 1 N sodium hydroxide.The reaction was allowed to warm to room temperature and stirred for 2hours. The reaction was diluted with methylene chloride and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent under reduced pressure and column chromatography ofthe residue on silica gel with 2% methanol/dichloromethane afforded 0.32g (35%) of product as a white solid. FAB MS [M+H] m/z; Calcd: 295,Found: 295

b. 3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-t-butyl-acetate.

To a solution containing 0.30 g (1.02 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one in 20 mL of DMF under anitrogen atmosphere was added 0.15 mL (1.02 mmol) of t-butylbromoacetate and 0.24 g (1.02 mmol) of silver oxide. The reaction washeated to 70° C. and maintained overnight. The reaction mixture wasdiluted with acetonitrile and filtered through a pad of celite. Thefiltrate was concentrated under reduced pressure and the residuepartitioned between ethyl acetate and water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel withdichloromethane afforded 0.20 g (48%) or product as a white solid. FABMS [M+H] m/z; Calcd: 409, Found: 409.

c. 3-[(Benzyloxycarbonyl)amino]-1-carboxymethylene-quinoline-2-one.

To a solution containing 1.30 g (3.18 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-t-butyl-acetate in 35 mLof dichloromethane under a nitrogen atmosphere at 0° C. was added 2.45mL (31.84 mmol) of trifluoroacetic acid. The reaction was allowed towarm to room temperature overnight. The solvent was removed underreduced pressure to afford 1.09 g (97%) of the title compound. FAB MS[M+H] m/z; Calcd: 353, Found: 353

d.3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 1.09 g (3.09 mmol) of3-[(benzyloxycarbonyl)amino]-1-carboxymethylene-quinoline-2-one in 50 mLof anhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphereat 0° C. was added 0.84 (3.31 mmol) of BOPCI and 1.10 mL (6.31 mmol) ofDIEA. After stirring for 30 minutes, 0.82 g (2.65 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2(S)-amino-3-methylbutan-1-olhydrochloride in 8 mL of dichloromethane and 0.56 mL (3.20 mmol) of DIEAwas added. The reaction was allowed to stir at 0° C. overnight, dilutedwith dichloromethane and washed with water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel with 5%methanol/dichloromethane afforded 0.37 g (30.3%) of product. FAB MS[M+H] m/z; Calcd: 610, Found: 610

Example 50 (CE-2107)3-[(Benzyloxycarbonyl)amino]-7-piperidinyl-quinoline-2-one-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 48. FAB MS [M+H] m/z;Calcd: 691, Found: 691 Example 51 (CE-2117)3-Carbomethoxy-4-fluoro-quinoline-2-one-N[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 48. FAB MS [M+H] m/z;Calcd: 535, Found: 535 Example 52 (CE-2113)3-(Amino-quinoline-2-one)-N[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 2.30 g (3.79 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-carbonyl)-2-(S)-methyl propyl]acetamide in 60mL of trifluoroacetic acid under a nitrogen atmosphere at 0C was added0.53 mL (4.54 mmol) of thioanisole. The reaction was allowed to warm toroom temperature overnight. The solvent was removed under reducedpressure. Subsequent preparative HPLC afforded 0.61 g (27%) of the titlecompound. FAB MS [M+H] m/z; Calcd: 474, Found: 474

Example 53 (CE-2116) 3-[(4-Morpholino)aceto]amino-quinoline-2-one-N[1-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 0.32 g (1.22 mmol) of 4-morpholino acetic acidin 18 mL of dichloromethane under a nitrogen atmosphere at 0° C. wasadded 0.33 g (1.30 mmol) of BOPCI and 0.22 mL (1.26 mmol) of DIEA. Afterstirring for 1.5 hours, a solution containing 0.61 g (1.04 mmol) of3-(amino-quinoline-2-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methypropyl]acetamidein 20 mL of dichloromethane was added followed by 0.22 mL (1.26 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand preparative HPLC afforded 0.20 g (27%) of the title compound. FAB MS[M+H] m/z; Calcd: 602, Found: 602

Example 54 (CE-2088)3,4-Dihydro-quinoline-2-one-N[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-N-methylpropyl]acetamidefrom commercially available 3,4-Dihydro-2(1H)-quinoline-2-one. Preparedin a similar manner as shown in Example 52. FAB MS [M+H] m/z; Calcd:461, Found: 461 Example 55 (CE-2099) 1-Acetyl-3-benzylidenepiperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 0.55 g (4.15 mmol) of N-chlorosuccinimide in 35mL of anhydrous toluene at 0° C. under a nitrogen atmosphere was added0.46 mL (6.22 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the additionof a solution containing 0.58 g (1.04 mmol) of 1-acetyl-3-benzylidenepiperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 8 mL of toluene. The reaction was allowed to stir at -25° C. for 2 h,followed by the addition of 0.68 mL (4.87 mmol) of triethylamine. Thecold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 40 minutes. The reaction was partitionedbetween ethyl acetate and water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel 60% ethylacetate/hexane gave 0.54 g of a brown oil which was further purified viapreparative HPLC to give 146 mg (25%) of the title compound. FAB MS[M+H] m/z; Calcd: 558, Found: 558

The intermediate 1-acetyl-3-benzylidenepiperazine-2,5-dione-N[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a. 1-Acetyl-3-benzylidene piperazine-2,5-dione-N-t-butyl acetate.

To a solution containing 6.36 g (26.00 mmol) of 1-Acetyl-3-benzylidenepiperazine-2,5-dione described by D. Villemn, et al. (SyntheticCommunications, 20:3325 (1990)), in 100 mL of DMF under a nitrogenatmosphere was added 9.62 mL (65.10 mmol) of t-butyl bromoacetate and7.55 g (32.60 mmol) of silver oxide. The reaction was heated to 45° C.overnight. The reaction was filtered through a plug of celite and thefiltrate concentrated under reduced pressure. The residue was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel with 1%methanol/dichloromethane gave 5.37 g of a tan solid. Furtherpurification via preparative HPLC gave 2.5 g (27%) of the titlecompound. FAB MS[M+H]m/z; Calcd: 359, Found: 359.

b. 1-Acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione.

To a solution containing 2.50 g (6.98 mmol) of 1-acetyl-3-benzylidenepiperazine-2,5-dione-N-t-butyl acetate in 100 mL of dichloromethaneunder a nitrogen atmosphere at 0° C. was added 5.40 mL (69.80 mmol) oftrifluoroacetic acid. The reaction was allowed to warm to roomtemperature overnight. The solvent was removed under reduced pressureand the residue diluted with ethyl acetate and washed with a saturatedsodium bicarbonate solution. The aqueous phase was acidified with 1 Nhydrochloric acid and extracted with ethyl acetate. The organic phasewas dried over magnesium sulfate. Filtration and removal of solventunder reduced pressure gave 1.96 g (96%) of product as a tan solid. FABMS [M+H] m/z; Calcd: 303, Found: 303.

c. 1-Acetyl-3-benzylidenepiperazine-2,5-dione-N-[1-(2[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 0.65 g (2.14 mmol) of1-acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione in 40 mLof anhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphereat 0° C. was added 0.57 g (2.24 mmol of BOPCI and 0.39 mL (2.21 mmol) ofDIEA. After stirring for 30 minutes, a solution containing 0.57 g (1.83mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 0.39 mL (2.21 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 5%methanol/dichloromethane gave 0.13 g (58%) of product. FAB MS[M+H] m/z;Calcd: 560, Found: 560.

Example 56 (CE-2105) 1-Acetyl-3-(4-fluorobenzylidene)piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 576, Found: 576. Example 57 (CE-2111) 1-Acetyl-3-(4-dimethylaminobenzylidene)piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 601, Found: 601. Example 58 (CE-2112) 1-Acetyl-3-(4-carbomethoxybenzylidene)piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 616, Found: 616. Example 59 (CE-2114)1-Acetyl-3-[(4-pyridyl)methylene]piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 559, Found: 559. Example 60 (CE-2144)4-[1-Benzyl-3-(R)-benzyl-piperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 2.20 g (16.48 mmol) of N-chlorosuccinimide in100 mL of anhydrous toluene under a nitrogen atmosphere at 0° C. wasadded 2.1 mL (28.59 mmol) of dimethyl sulfide. The reaction was cooledto -25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of a solution containing 2.5 g (4.10 mmol) of4-[1-benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 15 mL of toluene. The reaction was allowed to stir at -25° C. for 2hours, followed by the addition of 4.0 mL (28.70 mmol) of triethylamine.The cold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 30 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reducedpressure, and column chromatography of the residue on silica gel with 5%methanol/dichloromethane afforded 2.27 g of a light brown solid whichwas further purified via preparative HPLC to give 350 mg (14.4%) of thetitle compound. FAB MS [M+H]m/z; Calcd: 608, Found: 608.

The intermediate 4-[1-benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a. 1-Benzyl-3-(R)-benzylpiperazine-2,5-dione-4-t-butyl acetate.

To a solution containing 7.0 g (23.78 mmol) of 1-benzyl-3-(R)-benzylpiperazine-2,5-dione described by Steele, et al. (J. Biorg, Med. Chem.Lett., 5:47 (1995)) in 125 mL of DMF under a nitrogen atmosphere wasadded 5.30 mL (35.89 mmol) of t-butyl bromoacetate and 6.80 g (29.34mmol) of silver oxide. The reaction was heated to 50° C. overnight,diluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 50% ethyl acetate/hexane afforded 7.74 g (79.7%) of the titlecompound as a white solid. FAB MS[M+H]m/z; Calcd:409,Found::409.

b. 1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-dione.

To a solution containing 7.70 g (18.85 mmol) of 1-Benzyl-3-(R)-benzylpiperazine-2,5-dione-4-t-butyl acetate in 300 mL of dichoromethane undera nitrogen atmosphere at 0° C. was added 19.0 mL(191.30 mmol) oftrifluroacetic acid. The reaction was allowed to warm to roomtemperature overnight. The solvent was removed under reduced pressureand the residue dissolved in ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration and removalof solvent under reduced pressure afforded 6.69 g of product. FABMS[M+H]m/z; Calcd:353,Found:353.

c. 4-[1-Benzyl-3(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

To a solution containing 2.0 g (5.68 mmol) of1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-dione in 100 mLof dichloromethane and 2 mL of DMF under a nitrogen atmosphere at 0° C.was added 2.0 g (7.86 mmol) of BOPCI and 1.50 mL (8.62 mmol) of DIEA.After stirring for 30 minutes, a solution containing 1.80 g (5.7 mmol)of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 4.0 mL (22.99 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 7%methanol/dichloromethane afforded 2.69 g (77.7%) of product. FABMS[M+H]m/z; Calcd:610, Found: 610.

Example 61 (CE-2128)4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:608, Found: 608. Example 62 (CE-2146)4-[1-Benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:662, Found: 662. Example 63 (CE-2129)4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:662, Found: 662. Example 64 (CE-2133)4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[1-(3-[5-(2-dimethylaminoethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:575, Found: 575. Example 65 (CE-2084)4-[1-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:572, Found: 572. Example 66 (CE-2106)4-[1-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:518, Found: 518. Example 67 (CE-2162) 4-[1-(2-N-Morpholinoethyl)-3-(R)-benzyl piperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:631, Found: 631. Example 68 (CE-2149)5-(R,S)-Phenyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 0.28 g (2.10 mmol) of N-chlorosuccinimide in 50mL of anhydrous toluene under a nitrogen atmosphere at 0° C. was added0.23 mL (3.13 mmol) of dimethyl sulfide. The reaction was cooled to -25°C. using a carbon tetrachloride/dry ice bath, followed by the additionof a solution containing 0.26 g (0.52 mmol) of5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 10 mL of toluene. The reaction was allowed to stir at -25° C. for 2hours, followed by the addition of 0.30 mL (2.15 mmol) of triethylamine.The cold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 30 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue of silica gel with 10%methanol/dichloromethane, followed by preparative HPLC gave 120 mg(47.2%) of the title compound. FAB MS[M+H]m/z; Calcd:490, Found: 490.

The intermediate5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

a. (R)-N-(Ethoxy carbonylmethyl)-N'-(1-methoxy carbonyl-2-phenyl)urea.

To a solution containing 18.45 g (91.49 mmol) of (R)-2-phenylglycinemethylester in 250 mL of ethyl acetate and 13.4 mL (96.12 mmol) oftriethylamine under a nitrogen atmosphere at 0° C. was added 10 mL(91.49 mmol) of ethyl isocyanatoacetate. After stirring for 1h, thereaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration and removalof solvent under reduced pressure afforded 29.28 g (97.6%) of product asa white solid. FAB MS[M+H]m/z; Calcd: 235, Found: 235.

b. (R)-5-Phenyl-3-carboxymethyl hydantoin.

A mixture containing 29.28 g (99.49 mmol) of (R)-N-(ethoxycarbonylmethyl)-N'-(1-methoxy carbonyl-2-phenyl)urea in 500 mL ofconcentrated hydrochloric acid was heated to reflux overnight. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent under reduced pressure afforded 14.01 g (60%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 295, Found: 295.

c.5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide

To a solution containing 2.55 g (10.89 mmol) of(R)-5-phenyl-3-carboxymethyl hydantoin in 100 mL of dichloromethane and10 mL of DMF under a nitrogen atmosphere at 0° C. was added 2.30 g(12.00 mmol) of EDCI and 1.62 g (11.99 mmol) of HOBT. After stirring 30minutes, a solution containing 4.43 g (14.21 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 20 mL of dichloromethane and 4.78 mL (43.50 mmol) ofNMM. The reaction was allowed to warm to room temperature overnight,diluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 50% acetone/dichloromethane afforded 1.90 g (35.5%) of the titlecompound. FAB MS [M+H] m/z; Calcd: 490, Found: 490.

Example 69 (CE-2154)5-(S)-Benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 504, Found: 504. Example 70 (CE-2142)5-(R)-Benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 504, Found: 504. Example 71 (CE-2141)5-(R)-Benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 558, Found: 558. Example 72 (CE-2155)5-(S)-Benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 558, Found: 558. Example 73 (CE-2151)1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 594, Found: 594. Example 74 (CE-2150)1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 648, Found: 648. Example 75 (ONO-PO-698)2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 410 mg (0.744 mmol, 77% purity) of Dess-MartinReagent (1,1,1-triacetoxy-1,1-dihydro-1,2,benziodoxol-3-(1H)-one) in 4mL of dichloromethane was added dropwise a solution containing 410 mg(0.676 mmol) of2-[5-benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 5 mL of dichloromethane. The reaction mixture was allowed to stir for1 hour. The reaction was quenched by addition of water, extracted withethyl acetate (×2). The extract was washed with water and a saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using aelution of 33% ethyl acetate/hexane to afford 372 mg of the tittlecompound. APCI, Pos, 40V [M+H] m/z; Calcd: 605, Found: 605.

The intermediate2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows: to a solution containing 265 mg (1.01 mmol) of[1-[5-tert-butyl-1,3,4-oxadiazol-2-yl]-2-(S)-amino-1-hydroxy-3-methylbutanehydrochloride and 336 mg (0.843 mmol) of5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]aceticacid (J. Med. Chem., 38:98 -108 (1995)) in 2 mL of anhydrous DMF wasadded 155 mg (1.01 mmol) of HOBT and 231 mg (1.01 mrnol) of EDCl. Themixture was cooled to 0° C. and 0.11 mL (1.0 mmol) of NMM was addeddropwise and the reaction mixture was allowed to stir for 3 hours. Thereaction was quenched by addition of water and extracted with ethylacetate (×3). The extract was washed with aqueous 10% citric acidsolution, a saturated sodium hydrogencarbonate solution and a saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using agradient elution of 0 to 1% methanol/chloroform to afford 418 mg of thetittle compound. APCI, Pos, 40V [M+H] m/z; Calcd: 607, Found: 607.

Example 76 (ONO-PO-690)2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 667, Found: 667. Example 77 (ONO-PO-697)2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. El, Pos, [M+H] m/z;Calcd: 624, Found: 624. Example 78 (ONO-PO-716)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M-H]m/z; Calcd: 454, Found: 454. Example 79 (ONO-PO-722)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M-H]m/z; Calcd: 516, Found: 516. Example 80 (ONO-PO-727)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 456, Found: 456. Example 81 (ONO-PO-730)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M-H]m/z; Calcd: 436, Found: 436. Example 82 (ONO-PO-731)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M-H]m/z; Calcd: 498, Found: 498. Example 83 (ONO-PO-732)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 438, Found: 438. Example 84 (ONO-PO-734)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 454, Found:454. Example 85 (ONO-PO-735)2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 436, Found:436. Example 86 (ONO-PO-737)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 438, Found:438. Example 87 (ONO-PO-696)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

To a mixture containing 296 mg (0.49 mmol) of2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamideand 0.32 niL (2.9 mmol) of anisole in 8 mL of dichloromethane at OEC wasadded dropwise a solution containing 392 mg (2.9 mmol) of aluminumchloride in 4 mL of nitromethane. The reaction mixture was allowed tostir for 1.5 hours, quenched by addition of ice water, extracted withethyl acetate (×3). The extract was washed with water and a saturatedsodium chloride solution. The organic phase was dried over anhydrousmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using aelution of 66% ethyl acetate/hexane to afford 175 mg of the tittlecompound as a white solid. APCI, Pos, 40V [M+H] m/z; Calcd: 471, Found:471.

Example 88 (ONO-PO-691)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos, [M+H] m/z;Calcd: 533, Found: 533. Example 89 (ONO-PO-692)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos, [M+H] m/z;Calcd: 547, Found: 547. Example 90 (ONO-PO-693)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos, [M+H] m/z;Calcd: 519, Found: 519. Example 91 (ONO-PO-694)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 491, Found: 491. Example 92 (ONO-PO-695)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 492, Found: 492. Example 93 (ONO-PO-699)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 521, Found: 521. Example 94 (ONO-PO-701)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl)-3,4-dihydroxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 565, Found: 565. Example 95 (ONO-PO-703)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 505, Found: 505. Example 96 (ONO-PO-704)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 429, Found: 429. Example 97 (ONO-PO-705)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 457, Found: 457. Example 98 (ONO-PO-706)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 471, Found: 471. Example 99 (ONO-PO-707)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 453, Found: 453. Example 100 (ONO-PO-711)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-α,.alpha.-dimethybenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 515, Found: 515. Example 101 (ONO-PO-712)2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd:454, Found:454. Example 102 (ONO-PO-714)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-[1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 469, Found: 469. Example 103 (ONO-PO-715)2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(.alpha.,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 516, Found: 516. Example 104 (ONO-PO-718)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 471, Found: 471. Example 105 (ONO-PO-721)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 533, Found: 533. Example 106 (ONO-PO-728)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Neg, 40V [M-H]m/z; Calcd:449, Found:559. Example 107 (ONO-PO-729)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd:453, Found:453. Example 108 (ONO-PO-733)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd:471, Found:471. Example 109 (ONO-PO-736)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd:453, Found:453. Example 110 (ONO-PO-700)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

To a mixture containing 66 mg (0.093 mmol) of2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide(the compound prepared in a similar manner to Example 75) was added 2.5mL of 30% hydrobromic acid in acetic acid solution. The reaction mixturewas allowed to stir for 1 hour, quenched by addition of ice water,extracted with ethyl acetate (×3). The extract was washed with water(×2) and a saturated sodium chloride solution. The organic phase wasdried over anhyudrous sodium sulfate, filterd and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using a gradient elution of 0 to 1% methanol/chloroform toafford 41 mg of the title compound. El, Pos, [M+] m/z; Calcd:576,Found:576.

Example 111 (ONO-PO-702)2-[5-(Methylsulfonyl)amino-6-oxo-2-(4-fluorphenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

To a mixture containing 187 mg (0.36 mmol) of2-[5-amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide(the compound prepared in Example 25) in 3.5 mL of pyridine at 0EC underan atmosphere of argon was added 0.028 mL (0.36 mmol) of mesyl chloride.The reaction mixture was allowed to stir for 17 hours at roomtemperature, 15 hours at 50EC and 1 hour at 70EC. The reaction mixturewas quenched by addition of ice water, extracted with dichloromethane.The extract was washed with a saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution of 50 to 66% ethylacetate/hexane to afford 60 mg of the tittle compound. APCI, Pos, 40V[M+H] m/z; Calcd: 597, Found: 597.

Example 112 In Vitro Inhibition of Elastase

The following protocol was used to determine inhibitory activity ofONO-PO series of compounds. The elastase used in the protocol wasderived from human sputum (HSE). A mother solution of the HSE enzyme wasprepared from commercially available HSE (875 U/mg protein, SE-563,Elastin Product Co., Inc, Missouri, USA) by diluting with saline to1,000 U/ml, which was further diluted to 2 U/ml at 0° C. prior to use.

A solution was prepared by mixing 100 μl 0.2 M HEPES-NaOH buffer (pH8.0), 40 μl 2.5 M NaCl, 20 μl 1% polyethyleneglycol 6000, 8 μl distilledwater, 10 μl of a DMSO solution of inhibitor and 2 μl solution ofN-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroaniline (SEQ ID NO:1) (atconcentrations of 100, 200 and 400 μM). The solution was incubated for10 minutes at 37° C. To this was added an enzyme solution of HSE(elastase derived from human sputum). The resulting mixture wassubjected to the following rate assay.

Optical density (SPECTRA MAX 250, Molecular Devices) at 405 nm due top-nitroaniline generated by the enzyme reaction was measured at 37° C.in order to measure the reaction rate during the period that theproduction rate of p-nitroaniline remains linear. The rate, mO.D./min.,was measured for 10 minutes at 30 second intervals immediately after theaddition of the enzyme solution. IC₅₀ values were determined bylog-logit method and converted to K_(i) values by Dixson plot method.The values are presented in Table 2 below. Table 2.

    ______________________________________                                                 Ki                               K.sub.i                               Compound (nM) Compound K.sub.i  (nM) Compound (nM)                          ______________________________________                                        ONO-PO-690                                                                             78.3   ONO-PO-710 2.39  ONO-PO-730                                                                             23.5                                  ONO-PO-691 0.52 ONO-PO-711 2.55 ONO-PO-731 4.02                               ONO-PO-692 1.37 ONO-PO-712 16.6 ONO-PO-732 62.2                               ONO-PO-693 2.71 ONO-PO-713 12 ONO-PO-733 11.8                                 ONO-PO-694 24.8 ONO-PO-714 15.3 ONO-PO-734 43.8                               ONO-PO-695 13.9 ONO-PO-715 3.54 ONO-PO-735 26.4                               ONO-PO-696 6.38 ONO-PO-716 44.3 ONO-PO-736 6.43                               ONO-PO-697 27.3 ONO-PO-717 57.8 ONO-PO-737 36.3                               ONO-PO-698 0.77 ONO-PO-718 26.2                                               ONO-PO-699 21.2 ONO-PO-719 836.3                                              ONO-PO-700 1.18 ONO-PO-720 25.9                                               ONO-PO-701 2.98 ONO-PO-721 13.5                                               ONO-PO-702 1.78 ONO-PO-722 3.35                                               ONO-PO-703 2.25 ONO-PO-723 163.1                                              ONO-PO-704 14.0 ONO-PO-724 14.4                                               ONO-PO-705 10.7 ONO-PO-725 4281.4                                             ONO-PO-706 6.76 ONO-PO-726 589.5                                              ONO-PO-707 3.59 ONO-PO-727 132.8                                              ONO-PO-708 729.9 ONO-PO-728 8.75                                              ONO-PO-709 25.7 ONO-PO-729 29.1                                             ______________________________________                                    

CE compounds were tested as described in WO 96/16080. Results arepresented in Table 2 below. As shown, the compounds of the invention arepotent inhibitors of elastase, with certain compounds showingsubnanomolar levels of inhibitory activity.

Example 113 Blood Level Screening

The inhibitors were dissolved or suspended in polyethylene glycol (PEG),PEG-400 or PEG:H₂ O:EtOH at a concentration of 10 mg/ml. Unfasted maleSprague-Dawley rats were given an oral dose of this solution by gavage.Rats received 10 mg inhibitor/kg 10 body weight in a volume of 1 ml/kg.After 1,3 or 6 hr., the rats were killed with an overdose of urethane(2.5 g/kg; i.p.) and the blood collected in a heparinized tube viacardiac puncture. Red blood cells were separated from the plasma bycentrifligation.

Depending on the inhibitor, one of four organics (ethyl acetate,toluene, isopropyl ether or methyl t-butyl ether) was used to extractthe compound from the plasma. Inhibitor concentrations were measured byHPLC or LC/MS analysis. The results are presented in Table 3 below.Certain compounds of the invention demonstrate high levels of oralbioavailability as shown by their blood level concentrations over time.

Example 114 Extracellular Matrix (ECM) Assay Procedure

Forty-eight well plates on which extracellular matix had beenestablished were supplied to Cortech by Dr. Simon's group at the StateUniversity of New York at Stony Brook. Briefly, the plates were preparedas follows: R22 rat heart smooth muscle cells were seeded into wells at2.5×10⁴ cells/cm. The cells were fed every 4 days with Eagle's MinimalEssential Media supplemented with fetal bovine serum, tryptose phosphatebroth, cefotaxime and streptomycin. At confluence, daily supplements of50 ug/ml ascorbic acid were added for 8 to 10 days during the synthesisof the ECM layer. [³⁵ S]sulfate and [³ H]proline were also added to theculture media to incorporate radiolabel into the matrix. Cells werelater lysed with 25 mM NH₄ OH. Plates were washed three times with waterand once with phosphate-buffered saline containing 0.02% NaN₃. Plateswere stored at 4° C. until use.

Matrix degradation assays were performed as follows: 0.40 ml of Hanksbalance salt solution (HBSS) containing 1 or 5 uM test inhibitor (finalconcentration; diluted from DMSO stock solution; <2% DMSO finalconcentration) was added to the wells. After 30 minutes, 50 ul of apolymorphoneucleocyte (PMN) suspension was added resulting in 5×10⁵cells/well. PMN's were stimulated with opsonized zymosan. Zymosanparticles were washed and suspended in 0.5 ml human serum for 1 hr at37° C., vortexing every 15 min. The particles were then washed threetimes with HBSS and added to wells at a ratio of 10 particles/PMN in avolume of 50 ul. After a 4 hr incubation at 37° C., a 100 ul aliquot ofthe supernatant was withdrawn for scintillation counting. Followingremoval of the remaining supernatant, the residual ECM was solubilizedwith 0.5 ml 2M NaOH. The amount of tritium in this solubilized ECM wasaccessed by scintillation. ECM degradation data are expressed as(soluble counts released/total ECM counts)-(basal counts releasedwithout PMN's/total ECM counts). The results are presented in Table 3below.

                  TABLE 3                                                         ______________________________________                                        HNE K.sub.i                                                                             ECM Data % Inhibition                                                                        Plasma Levels (μM)                                CE #  (nM)    1 uM     5 uM    1 hr  3 hr  6 hr                               ______________________________________                                        CE2048                                                                              0.2                                                                       CE2049 0.5                                                                    CE2050 1.84                                                                   CE2051 1.56                                                                   CE2052 0.37                                                                   CE2053 0.41                                                                   CE2054 0.29                                                                   CE2055 0.49    0.002                                                          CE2056 0.98                                                                   CE2057 0.375                                                                  CE2058 0.564                                                                  CE2061 71600                                                                  CE2062 0.3                                                                    CE2064 0.44                                                                   CE2065 0.47                                                                   CE2066 0.98                                                                   CE2067 3.6                                                                    CE2068 800                                                                    CE2069 4.4                                                                    CE2072 0.025 64.8 74.55 0.277 0.115 0.061                                     CE2073 0.235                                                                  CE2074 1                                                                      CE2075 0.039                                                                  CE2076 1.5                                                                    CE2077 0.15                                                                   CE2078 1.05                                                                   CE2079 34                                                                     CE2080 62                                                                     CE2082 53                                                                     CE2083 73                                                                     CE2084 133                                                                    CE2087 20                                                                     CE2088 66   0.801 0.755                                                       CE2089 1.5                                                                    CE2090 2.7                                                                    CE2091 270                                                                    CE2092 6.3                                                                    CE2093 0.26                                                                   CE2094 10                                                                     CE2095 0.21 60.43 55.63                                                       CE2096 0.79                                                                   CE2097 115                                                                    CE2098 85                                                                     CE2099 1.9    0.042                                                           CE2100 0.069 57.63 56.56  0.064                                               CE2101 0.64 44.582 51.18 1.238 1.369 1.042                                    CE2102 258                                                                    CE2103 12.4                                                                   CE2104 0.33                                                                   CE2105 0.72                                                                   CE2106 41                                                                     CE2107 17                                                                     CE2108 10.5                                                                   CE2109 126                                                                    CE2110 0.13                                                                   CE2111 20    0.69                                                             CE2112 1.2                                                                    CE2113 39   1.835 0.909                                                       CE2114 25                                                                     CE2115 1                                                                      CE2116 76                                                                     CE2117 586                                                                    CE2118 13.2                                                                   CE2119 7.7                                                                    CE2120 51                                                                     CE2121 28                                                                     CE2122 63                                                                     CE2123 15                                                                     CE2124 0.033                                                                  CE2125 0.4    0.011                                                           CE2126 5    0.161                                                             CE2127 34                                                                     CE2128 64                                                                     CE2129 300                                                                    CE2130 2.1 16.32 29.02  0.162                                                 CE2131 265                                                                    CE2132 23.5                                                                   CE2133 33000                                                                  CE2134 2 21.71 25.724  5.02                                                   CE2135 17.5 0 37                                                              CE2136 104                                                                    CE2137 558                                                                    CE2138 294                                                                    CE2139 41                                                                     CE2140 204                                                                    CE2141 64    0.005                                                            CE2142 8.7                                                                    CE2143 11.5                                                                   CE2144 9.3                                                                    CE2145 0.038                                                                  CE2146 67                                                                     CE2147 1600                                                                   CE2149 0.28 51.275 55.9 0 0 0                                                 CE2151 59 14.25 -8.3                                                          CE2152 0.24                                                                   CE2154 10 54.6 65.4                                                           CE2155 57                                                                     CE2156 512                                                                    CE2157 1.4 9.96 13.42  3.81                                                   CE2159 52                                                                     CE2160 260                                                                    CE2161 0.082 25 55                                                            CE2162 10.6    0.025                                                          CE2163 0.75 54.7 64  0.316                                                    CE2164 17    0.034                                                            CE2165 2.6    0.067                                                           CE2166 145                                                                    CE2168 0.15                                                                   CE2170 297                                                                    CE2171 0.64                                                                   CE2172 2.2    0.021                                                           CE2173 6.5 35.9 47.1                                                          CE2174 15.2 1.49 18.3 1.86 0.97                                               CE2176 52                                                                     CE2177 0.016 74.2 76.78 0.393 0.41 0                                          CE2178 0.29  34  0.185                                                        CE2179 7.6 48.8 45.9 1.229 0.599                                              CE2180 44                                                                     CE2181 46                                                                     CE2182 54                                                                     CE2183 0.23                                                                   CE2184 8.2 30.5 32.4  0.57                                                    CE2185 0.27                                                                   CE2186 0.037                                                                  CE2187 42                                                                     CE2189 99                                                                     CE2190 29                                                                     CE2191 85 29.35 30.5                                                          CE2192 7.3 40.8 49.7                                                          CE2193 36                                                                     CE2194 2.4 41 58.7 1.11 0.553                                                 CE2195 10.6                                                                   CE2196 96                                                                     CE2197 4.8                                                                    CE2198 3.1                                                                    CE2200 13.7                                                                   CE2202 0.12                                                                   CE2203 79    0.004                                                            CE2204 7.4    0.48                                                            CE2205 37    0.475                                                            CE2206 8.7 47.4 62.3                                                          CE2207 1.2    0                                                               CE2208 40                                                                     CE2209 36.4    0                                                              CE2210 22.7                                                                   CE2211 348                                                                    CE2212 124                                                                    CE2213 0.14    0.19                                                           CE2214 0.92    0                                                              CE2215 163   1.16 0.83 0.63                                                   CE2216 4.1 32.1 37.15 0.77 0.47 0.25                                          CE2217 5.5 28.1 41.2 1.99 0.521                                               CE2218 1.6 30.5 33.15                                                         CE2219 537                                                                    CE2220 52                                                                     CE2221 34                                                                     CE2223 0.93 34.15 36.15                                                       CE2224 1 43.25 66.8 1.843 1.943 1.961                                         CE2225 8.2 30.85 43.45                                                        CE2226 10.3 27.55 52.25                                                       CE2227 40   1.276 0.74 0.962                                                  CE2228 40   0.714 1.393 0.409                                                 CE2229 9.5 31.25 48.2                                                         CE2230 2.6 37.7 37.8  0                                                       CE2231 16   1.226 0.787 0.531                                                 CE2232 0.15   0.44 0.44 0.26                                                  CE2233 41.6 54.7 55.4 0.07 0.065 0.036                                        CE2234 796 39.7 35                                                            CE2235 9.5 19.75 13.25                                                        CE2236 7.1 31.9 31.75                                                         CE2237 3 34.6 42.6 1.02 1.8 0.84                                              CE2238 162 10.1 18.8 2.573 1.739 1.028                                        CE2239 43 11.9 11.3 1.46 1.15 0.71                                            CE2240 30 16.8 13.5 1.12 0.5 0.29                                             CE2241 14 18.6 31.7 0.598 0.289 0.078                                         CE2242 27 29.4 40.7                                                           CE2243 11 48 54.9 2.801 2.104 1.598                                           CE2244 78.5                                                                   CE2245 24 34.7 39.3                                                           CE2246 18.5 -2.3 32.6 1.182 0.837 0.496                                       CE2247 62.4 13.3 21.2 1.017 0.572 0.186                                       CE2248 3.1 39.4 63.2 1.65 1.58 1.22                                           CE2249 13 22.4 42.4 1.179 0.704 0.213                                         CE2250 6.9 27.4 48.6                                                          CE2251 0.43 54.1 74.5 1.63 1.11 0.73                                          CE2252 1.9 45.4 65.2 0.114 0.188 0.1                                          CE2253 11 31.9 45.9 0.282 0.246 0.163                                         CE2254 2.4 57.2 58.4 1.751 1.575 2.316                                        CE2255 18 20.7 42                                                             CE2256 16 24 47.8 0.9 0.33 0.2                                                CE2257 30 48.3 61.4                                                           CE2258 3.7 42.9 38.1 1.624 1.5 1.212                                          CE2259 3.3 43 59.6 0.597 0.846 0.502                                          CE2260 0.39 68.3 59.7 3.532 3.053 1.894                                       CE2261 0.36                                                                   CE2262 0.42                                                                   CE2263 0.67                                                                 ______________________________________                                    

Example 115 Ex vivo Inhibition of Elastase

Sixty (60) minutes after the oral adminstration of an inhibitor with anappropriate vehicle, a blood sample (0.9 ml) is collected through theabdominal aorta by a syringe containing 0.1 ml of a 3.8% sodium citratesolution.

The blood sample is processed as follows: 60 μl of (final 0.1-1 mg/ml) asuspended solution of opsonized zymosan in Hank's buffer is added to thepreincubated whole blood (540 μl) for 5 minutes at 37° C., and theresulting mixture is incubated for 30 minutes at the same termperature.The reaction is terminated by immersing the test tube into ice water.The reaction mixture is then centrifuged at 3,000 rpm for 10 minutes at4° C. Twenty (20) μl each of the resulting supernatant (the Sample) ismeasured for elastase activity.

The mixture consisting of the following components is incubated for 24hours at 37° C., and then optical density is measured at 405 nm:

    ______________________________________                                        0.2M tris-HCl buffer (pH 8.0)                                                                      100 μl                                                  2.5M NaCl 40 μl                                                            Distilled water 36 μl                                                      50 mM solution of a substrate (*)  4 μl                                    The Sample 20 μl                                                         ______________________________________                                         (*) NMethylsuccinyl-Ala-Ala-Pro-Val-p-nitroanlide (SEQ ID NO: 1)         

A test sample mixed with 1-methyl-2-pyrrolidone instead of the substrateis regarded as Substrate (-). A test sample mixed with saline instead ofthe Sample is regarded as Blank. The remaining elastase activity in theSample is calculated according to the following:

optical density of Substrate (+)-(optical density of Substrate(-)+optical density of Blank) as a total production of p-nitroanilineover 24 hours based on a standard curve for the amount ofp-nitroaniline.

An average activity is calculated based on the test sample of 5-6animals. An agent at 3, 10 or 30 mg/kg is orally given by a forcedadministration to a 24 hour fasted animal at 60 minutes before the bloodsampling. Optical density is measured by SPECTRA MAX 250 (MolecularDevices).

    __________________________________________________________________________    #             SEQUENCE LISTING                                                   - -  - - <160> NUMBER OF SEQ ID NOS: 1                                        - - <210> SEQ ID NO 1                                                        <211> LENGTH: 4                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Human                                                         <220> FEATURE:                                                                <221> NAME/KEY: BLOCKED                                                       <222> LOCATION: (1)...(1)                                                     <223> OTHER INFORMATION: MeOSucc                                              <220> FEATURE:                                                                <221> NAME/KEY: BLOCKED                                                       <222> LOCATION: (4)...(4)                                                     <223> OTHER INFORMATION: p-nitroanilide                                        - - <400> SEQUENCE: 1                                                         - - Ala Ala Pro Val                                                        __________________________________________________________________________

We claim:
 1. A compound of the formula: ##STR34## wherin X and Y areindependently O, S or N, wherein N is optionally substituted with alkylor alkenyl optionally substituted with 1-3 halo atoms; (C₅ -C₆)aryl,arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selectedfrom N, O and S, and optionally substituted with halo, cyano, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl,alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,arylcarboxamide, alkylthio or haloalkylthio, provided that at least oneof X or Y is N;R₁ is alkyl, alkenyl or alkynyl optionally substitutedwith 1 or more halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino,dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide or --O--(C₅ -C₆)aryl; hydroxyl, amino,alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl,(C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl, (C₅ -C₁₂)arylalkenyl, fused(C₅-C₁₂)aryl-cycloalkyl or alkyl fused(C₅ -C₁₂)aryl-cycloalkyl optionallycomprising 1-4 heteroatoms selected from N, O and S, and optionallysubstituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio; R₂ and R₃ are independently or together H; alkyl oralkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio,amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl,guanidinyl, or amidylguanidine; --RCOR', --RCOOR', --RNR'R"R° or--RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° areindependently H, alkyl, alkenyl, cycloalkyl or (C₅ -C₆)aryl; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl,alkyl-thioaryl, alkyl-aminoaryl, (C₅ -C₁₂)aryl, (C₅ -C₁₂)arylalkyl or(C₅ -C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S, and optionally substituted with halo, cyano, keto, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl, --O--(C₅ -C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio; B is --S(O)₂ --, --C(O)--, --OC(O)-- or --CH₂ --C(O)--;and R₆ is aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, or is of formula(I) ##STR35## wherein m and n are independently 0 or 1; D is a directbond or an amino acid selected from proline, isoleucine,cyclohexylalanine, cysteine optionally substituted at the sulfur withalkyl, alkenyl or phenyl optionally substituted with halogen, cyano,nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy,haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,alkylthio or haloalkylthio; phenylalanine, indoline-2-carboxylic acid,tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl, haloalkenyl, alkynyl, halogen, cyano, nitro, haloalkyl,amino, aminoalkyl, dialkylamino, alkoxyl, haloalkoxy, carbonyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkyithio orhaloalkythio; tryptophan, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid; or lysine optionally substituted atthe side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl oralkoxycarbonylalkyl; or cycloalkyl, cycloalkylalkyl, fusedaryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1or more heteroatoms selected from N, O and S;A is a direct bond,--C(O)--, --NH--C(O)--, --S(O)₂ --, --OC(O)-- or --CH₂ --; and R₁₄ is H,alkyl, alkenyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fusedaryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1or more heteroatoms selected from N, O and S, and optionally substitutedwith alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy,alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,arylalkyl, arylcarboxamide, alkylthio or haloalkylthio.
 2. A compound ofclaim 1 wherein R₆ is of formula (I).
 3. A compound of claim 2 wherein Dis Val.
 4. A compound of claim 3 wherein R₁₄ --A is Cbz.
 5. A compoundof claim 4:Benzyloxycarbonyl-L-(1,2,3,4-tetrahydroisoquinoline)-3-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(R,S)-methylpropyl]amide.6. A compound of claim 1 wherein R₆ is aryl, arylalkyl, cycloalkyl, oralkylcycloalkyl.
 7. A compound of claim 6 wherein R₆ is arylalkyl.
 8. Acompound of claim 7 wherein R₆ --B-- is benzyloxycarbonyl.
 9. A methodof inhibiting one or more serine proteases comprising administering to ahost in need of such inhibition an effective amount of a compound ofclaim
 1. 10. A method of claim 9 wherein the serine protease inelastase.
 11. A method of claim 10 wherein the elastase is humanneutrophil elastase.
 12. A method of claim 9 wherein said compound isadministered orally.
 13. A pharmaceutical composition comprising one ormore compounds of claim 1 and a pharmaceutically acceptable carrier.